Experiments designed to elucidate cellular internalization of Pseudomonas aeruginosa exotoxin A are described. Inhibition of protein synthesis was used as an index of the biological activity of exotoxin A, and a biotinyl-toxin: avidin-gold system to follow its movement on the ultrastructural level. Addition of amantadine, methylamine and dansylcadaverine to cells enhanced the toxicity of exotoxin A at lower concentrations, while protecting cells at higher concentrations. In general, both sensitive and resistant cell lines responded similarly. Exposure of LM or Vero cells to an acidic extracellular pH did not overcome the protection afforded by ammonium chloride against exotoxin A cytotoxicity. This and other data suggest that sensitive and resistant cells may internalize exotoxin A in a similar manner, the toxin entering the cytosol from a prelysosomal acidic vacuole.