Uveitis is considered a rare complication of leptospirosis. This report describes an epidemic of uveitis among patients with leptospirosis and provides data, using polymerase chain reaction (PCR) amplification of Leptospira DNA, that the pathogenesis is associated with anterior chamber spirochetes. Forty-six uveitis patients, 49 uveitis controls, and 54 cataract controls were enrolled at Aravind Eye Hospital (Madurai, India). Leptospiral DNA was detected by PCR of aqueous humor; serum antibody titers were determined by ELISA and microagglutination (MAT). Thirty-seven uveitis patients (80%) demonstrated leptospiral DNA compared with 5 controls (8%; P < .001). Thirty-three uveitis patients (72%) had positive serology compared with 10 uveitis controls (20%) and 13 cataract controls (24%; P < .001). This report describes the largest cluster of patients with leptospiral uveitis and identifies six clinical characteristics that provide a diagnostic profile for leptospiral uveitis. This profile will be important for determining treatment regimens in countries where PCR and MAT are not available.