OBJECTIVES: Comparison of leflunomide, methotrexate and sulfasalazine  safety based on data from WHO Programme for International Drug Monitoring. METHODS: The data from countries participating in the World Health Organization Programme for International Drug Monitoring are collected and maintained, on behalf of the WHO, by the Uppsala Monitoring Centre, in the Vigibase. An analysis of data on adverse events (AE) of leflunomide, methotrexate and sulfasalazine reported to Vigibase since 2000 up to 16th March 2009 (ref: ER18-2009), was performed. RESULTS: The total number of 16,311 individual case reports of leflunomide adverse events were registered in the Vigibase, compared to 32,945 and 5,011 for methotrexate and sulfasalazine, respectively. There were 108 death cases registered for leflunomide, 236 for methotrexate and 18 for sulfasalazine. Most frequent system-organ classes reported were: gastro-intestinal system disorders (13.2%) and skin and appendages disorders (9,8%) for leflunomide, respiratory system disorders (11.6%) and general disorders (10.8%) for methotrexate and skin and appendages disorders (17.7%) and general disorders (14.6%) for sulfasalazine. Most frequent AE reports for leflunomide were: diarrhoea (588 cases versus 303 and 58 for methotrexate and sulfasalazine, respectively), dyspnoea (310 vs. 563 vs. 53), hepatic function abnormal (304 vs. 262 vs. 78), nausea (272 vs. 401 vs. 90), rash (270 vs. 181 vs. 209), hypertension (265 vs. 138 vs. 6) and anaemia (242 vs. 383 vs. 55). Congenital abnormalities were reported in 26 leflunomide, 204 methotrexate and 15 sulfasalazine patients. CONCLUSIONS: WHO data indicates that leflunomide is at least as safe as methotrexate. All three disease modifying drugs have different spectrum of adverse events.