A retrospective, matched case-control study was conducted in Jamaica's Western Regional Health Authority (WRHA). Forty-three individuals developing clinical leptospirosis between January 2005 and December 2007 (i.e., cases) were age and neighborhood matched to 89 controls. Odds ratios (OR) and associated 95% confidence intervals (CIs) and the relative excess risk due to interaction (RERI) were calculated. Cases had increased odds of contact with rodents OR 3.52, goats OR 3.38, and being engaged in outdoor labor OR 5.30. Knowledge of leptospirosis and indoor work was protective, OR 0.39 and OR 0.16, respectively. Positive RERI values were noted for joint exposure to rodents and goats (RERI 5.54), outdoor labor and goats (RERI 6.97), and outdoor labor and rodents (RERI 30.59). Our results suggest a synergistic effect of occupational and environmental exposures on clinical human leptospirosis from the WRHA. Knowledge of the disease and its risk factors allows for protection from the disease.