OBJECTIVE: To characterize the frequency, reasons, risk factors, and consequences of unstructured anti-retroviral treatment interruptions. METHOD: Systematic review. RESULTS: Seventy studies were included. The median proportion of patients interrupting treatment was 23% for a median duration of 150 days. The most frequently reported reasons for interruptions were drug toxicity, adverse events, and side-effects; studies from developing countries additionally cited treatment costs and pharmacy stock-outs as concerns. Younger age and injecting drug use was a frequently reported risk factor. Other risk factors included CD4 count, socioeconomic variables, and pharmacy stock outs. Treatment interruptions increased the risk of death, opportunistic infections, virologic failure, resistance development, and poor immunological recovery. Proposed interventions to minimize interruptions included counseling, mental health services, services for women, men, and ethnic minorities. One intervention study found that the use of short message service reminders decrease the prevalence of treatment interruption from 19% to 10%. Finally, several studies from Africa stressed the importance of reliable and free access to medication. CONCLUSION: Treatment interruptions are common and contribute to worsening patient outcomes. HIV/AIDS programmes should consider assessing their causes and frequency as part of routine monitoring. Future research should focus on evaluating interventions to address the most frequently reported reasons for interruptions.