Leptospirosis occurs as seasonal outbreaks, lasting for about 3 weeks during October-November in North Andaman. A randomized controlled trial was undertaken to assess the efficacy of doxycycline prophylaxis in the prevention of infection and clinical disease due to leptospires during the outbreak period. A sample population of 782 persons, randomized into two groups was given doxycycline 200 mg/week and a placebo. The microscopic agglutination test was done on blood samples collected on day zero, after 6 weeks and after 12 weeks. Infection rates and attack rates of clinical illness were calculated in the two groups based on the serological results. Statistically there was no difference in the infection rates among the two groups. However, a statistically significant difference was observed in the clinical disease attack rates (3.11 vs. 6.82%) between study group and control group. The results of the study indicate that doxycycline prophylaxis does not prevent leptospiral infection in an endemic area, but has a significant protective effect in reducing the morbidity and mortality during outbreaks.