Diphtheroids were generally regarded as nonpathogenic contaminants, but recent clinical studies have emphasized that they may cause serious systemic and ocular disease mostly in patients with underlying medical conditions. In this study we present a case report of acute onset endogenous endophthalmitis associated with heavy growth of diphtheroids on the culture of anterior chamber fluid sample in a 46-year-old man with uncontrolled diabetes mellitus. He did well after appropriate treatment and a functional vision was restored. This case highlights the importance of proper management for the outcomes of patients with endogenous endophthalmitis. It is also significant to be cautious about a life-threatening medical status in a patient with such presentation.