Megabacteria are large, Gram-positive, periodic acid Schiff (PAS)-positive, rod-shaped, non spore-forming, single-celled organisms. Neither their pathogenicity nor taxonomy has yet been determined. The organisms are frequently found in large numbers in the proventriculus of birds and have been associated with proventricular/ventricular disease (PVD), a debilitating, chronic wasting disease found in a wide range of birds both in Australia and overseas. The available literature relating to megabacteria and PVD is limited, frequently conflicting and of poor credibility. It was studied to determine any relevancy and presented in a review of the literature before a series of experimental investigations were discussed. The experimental investigations significantly advance scientific knowledge about an important, but poorly understood disease affecting caged and aviary birds, and provide the experimental results essential for future research in this area. The experimental components of the thesis investigated the characteristics of megabacteria, the prevalence of megabacteria in wild birds in Australia and the pathogenesis and treatment of megabacteria-associated PVD. New findings associated with the characteristics of megabacteria demonstrated that the organisms' cell surface was striated and intimately associated with a glycocalyx-like substance. Also, intracellular membrane­ bound bodies, which do not label for DNA, existed within megabacteria; instead, DNA was randomly distributed throughout the cells and concentrated in the nucleoid areas. Hence, the organisms were morphologically considered to be prokaryotae. Attempts to culture megabacteria found that, despite their prokaryotic morphology, the organisms could not be cultured on typical bacteriological culture media. Instead, some limited success was achieved in pre-reduced, anaerobic broth media typically used to grow yeasts, yet at a low pH. Investigations into the treatment for megabacteria-associated disease found that megabacteria were resistant to a wide range of antibacterial antibiotics, yet susceptible to the polyene macrolide antifungal agents, amphotericin Band nystatin. These results were unusual, because if megabacteria truly are the prokaryotae suggested by their morphology, the polyene macrolide antifungal agents should have had no effect. Genetic studies were subsequently employed in order to further investigate the nature of megabacteria, but the studies, despite functioning effectively, did not successfully produce the anticipated results. In conclusion, it was hypothesised that megabacteria are not prokaryotae or eukaryotae, but representatives of another, different domain of organisms, possibly the archaea or another as yet undetermined domain. The nature of megabacteria warrants further investigation concentrating on the acquisition of a pure culture of organisms for subsequent genetic tests. The incidence of megabacteria in wild birds in a remote region of Victoria, Australia, was found to be high in clinically healthy young cockatoos and goldfinches. This finding was significant, as the occurrence of the organisms in Australian wild birds had previously been speculated but not reported in the scientific literature. A series of studies into the pathogenesis of PVD reported a number of new findings. A definite relationship was demonstrated to exist between the presence of megabacteria and PVD in budgerigars. It was also shown that birds with PVD were not significantly compromised in their ability to digest the major nutritive components of the diet (fat, fibre, protein and ash). Subsequently, it was suggested that affected birds lost weight owing to reasons other than maldigestion, such as reduced feed intake. Megabacteria infection was shown to have no effect on the pH of the proventricular contents and birds with severe PVD were shown to be anaemic and hypoproteinaemic; findings that were to be expected considering the proventricular ulceration and haemorrhage, reduced feed intake and stress that are classic lesions and symptoms of PVD. In conclusion, despite being able to state definitively that megabacteria are associated with proventricular/ventricular disease, the role they play in the development of the disease was not determined within the scope of this thesis. The pathogenesis of megabacteria-associated PVD requires further investigation.