Background: Patient education is an important part of antiretroviral (ARV) treatment (ART) and plays a cardinal role in adherence to highly active ARV therapy. Aims: The objective was to compare a structured teaching method (STM) with traditional casual patient education method (TM) and evaluate its effectiveness on adherence to high activity ART (HAART), immunologic recovery, development of opportunistic infections (OI), hospitalization and mortality. Materials and Methods: This study was a hospital-based, prospective cohort study of 620 (296 subjects and 324 controls) consecutive human immunodeficiency virus patients admitted into the medical in-patient wards of the Federal Medical Centre, Ido-Ekiti, Nigeria, for various clinical conditions, between January 2006 and December 2012. A pre-test and post-test time series design were used for data collection using a 30-item knowledge and skills assessment schedule with items rated on a five-point Linkerttype scale. The schedule was pre-tested on 20 patients with Cronbach’s score of 0.92 and a test-retest co-efficient of 0.89 at a 2 weeks interval. P < 0.05 was considered significant. Results: Mean age was 28.7 ± 6.9 years. Mean adherence rate for the subjects was 98.9% ± 1.0% and for controls, 87.6% ± 2.4% (P < 0.001). CD4+ T-cell count increase was significantly more in subjects (238 vs. 141, P < 0.001). Frequency of OI per patient per month was lower in subjects than in controls (0.51 vs. 1.31, P = 0.002). Mean number of readmissions per patient was 0.18 ± 0.01 for subjects and 0.89 ± 0.02 for controls (P = 0.0012). Subject group had shorter hospital stay (P = 0.002) and lower mortality (P = 0.008) for the controls. Conclusion: STM has a significant effect on adherence to HAART, immunologic recovery, development of OI, re-admission rate, hospital stay and mortality. This teaching method is novel and should be recommended as a core aspect of patient adherence counseling and education in ART program in resource-poor settings and globally.