Acanthamoeba keratitis is treated with long-term biguanide therapy, and the treatment itself can lead to ocular side effects. Knowledge of possible toxic complications can help in the better titration of the treatment regimen. Here, we describe the toxic side effects of polyhexamethylene biguanide (PHMB), which occurred in three consecutive patients treated with in-house compounded PHMB. There was an error in compounding the solution, with the resultant concentration of PHMB being around 0.2%. Patients developed ocular toxicity like conjunctival inflammation, persistent epithelial defect, and large pigment clumps on endothelium within six weeks of initiation of therapy. All of them developed rapidly progressive cataract and mydriatic pupil within three months. PHMB has the potential to cause irreversible damage to ocular structures, and the toxicity is time and concentration-dependent.