BACKGROUND Infectious diseases remain among the major morbid events in patients with end-stage renal disease (ESRD) on renal replacement therapy (RRT). In developing countries, tuberculosis (TB) has been found to occur more frequently in these patients than in the general population. Efficacy of isoniazid (INH) chemoprophylaxis has been seen in other situations, such as human immunodeficiency virus infection. However, studies on INH prophylaxis in ESRD patients on RRT are limited. METHODS In this prospective randomized controlled trial, from April 2000 to June 2001, a total of 109 ESRD patients registered for renal transplant and accepted for maintenance hemodialysis in our hospital were included and followed up until June 2004 to assess the role of INH prophylaxis in preventing development of TB. At the time of acceptance for hemodialysis, 54 patients were assigned to receive daily INH for 1 year and 55 patients were assigned to the control group. Primary outcome was development of TB. Secondary outcome was INH hepatotoxicity. To evaluate the effect of INH prophylaxis on the development of TB, a Kaplan-Meier survival estimate was used to plot TB-free survival curve and log-rank test was used for comparison. RESULTS Overall, TB was diagnosed in 27 patients during RRT, with an incidence of 24.8%. TB developed in 9 (16.7%) patients in the INH group and in 18 (32.7%) patients in the control group. There was a significantly lower incidence of TB in the INH group as compared with the control group. The risk ratio of INH vs. control group for development of TB was 0.40 (95% confidence index [CI], 0.17-0.92; P=0.032). In the INH group 27 (50%) patients and in the control group 17 (30.9%) patients developed some hepatic dysfunction. However, significant hepatitis that required discontinuation of INH developed in only 9 (16.7%) patients in the INH group. Furthermore, significant hepatitis also developed in 6 (10.9%) patients in the control group. The majority of patients with significant hepatitis in both groups (INH as well as control) were subsequently found to be positive for hepatitis B and/or hepatitis C viral infection. Mild hepatitis (which did not require discontinuation of INH) was seen in 18 (33.3%) patients in the INH group and 11 (20%) patients in the control group. Viral hepatitis infection was not found in any of the milder cases of hepatitis in either group. CONCLUSION This study shows significant efficacy of INH chemoprophylaxis during RRT in preventing development of TB, when the INH was started during dialysis itself. INH chemoprophylaxis was safe and well tolerated in the majority of patients. However, mild hepatic dysfunction was common, both in the treatment as well as in the control group. As the incidence of viral hepatitis overall was high in our patients on RRT, it is difficult to identify INH-induced hepatitis in this clinical setting.