Objectives: The aim was to evaluate the utilization pattern, efficacy and safety of drugs prescribed for opportunistic infections (OIs) in human immunodeficiency virus (HIV) positive patients. Materials and Methods: In this observational, prospective, single center study, HIV positive patients were followed-up for a period of 1 year to record the OIs; their clinical course and outcome. Utilization pattern, efficacy and safety of the drugs used were evaluated. Rationality of treatment was assessed using National AIDS Control Organization and Standard Treatment Guidelines. Results: A total of 222 OIs were detected in 134 patients. Majority of patients (90.2%) were adults. The commonest OIs included tuberculosis (TB) (89), oropharyngeal candidiasis (OPC) (37), bacterial infections (30) and chronic diarrhea (22). Use of supportive drugs and empirical treatment of certain OIs contributed to a higher number of drugs (average of 3.5 drugs) per prescription. Drugs, prescribed in accordance with the above mentioned guidelines, were effective in most cases. Drugs were well-tolerated with only two serious adverse drug reactions (ADRs) reported. Majority of ADRs were associated with anti TB drugs. Conclusion: Tuberculosis, oropharyngeal candidiasis, bacterial infections and chronic diarrhea are the commonest OIs. Overall, a rational approach to therapy and good tolerability and efficacy of drugs was observed. Empirical treatment of infections should be minimized.