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Background: Highly active antiretroviral therapy (HAART) is complex and many factors contribute to a patient’s response to initial therapy including adherence, drug effectiveness, and tolerance. Close HAART follow-up is needed, particularly when there are concurrent therapies such as prophylactic antibiotics and medications for the treatment of comorbidities. Objective: To assess the effectiveness of pharmacist intervention in reducing drug related problems in HIV/AIDS outpatients (intervention group) and in improving clinical parameters in the intervention group compared to the control group. Methods: We conducted a prospective controlled intervention study with patients paired by gender and initial T CD4+ lymphocyte (CD4) count. HIV-infected patients of a public outpatient service were enrolled for the study by consecutive and convenience sampling. Patients selected for the study were divided into a control group and an intervention group. Both groups were followed for one year; however, only the intervention group received pharmaceutical care. The primary outcome was the drug related problem (DRP) analysis for the intervention group. Secondary outcomes were CD4 count and viral load evaluation for both groups. Results: There was a total of 143 patients enrolled in this study, with 53 (37.06%) patients in the control group and 90 (62.94%) patients in the intervention group. A total of 202 pharmacist interventions with 193 pharmacist-patient and 9 pharmacist-physician interventions were proposed. After one year of pharmaceutical care, a reduction of 38.43% between the initial and final DRP was found (p = 0.0001). The most common DRPs found were related to medication safety. The intervention group showed a mean increase of 84% for the CD4 count in comparison with that observed in the control group. The viral load was not significantly different between the final and initial mean values for both groups. Conclusion: Pharmacist appointments enabled identification, prevention, and solving of drug related problems, especially those related to drug safety. Also, pharmacist interventions improved adherence and increased HAART effectiveness as suggested by the higher elevation in the CD4 count seen in the intervention group in comparison with the control group.