Adherence to medication is of great concern in the management of HIV infected patients. Thus, Highly Active Antiretroviral Therapy (HAART) has demonstrated efficacy in suppressing HIV replication, improving immune function and reducing HIV-related morbidity and mortality. Thirty-seven HIV-infected Omani patients on HAART were enrolled into this prospective study but only 34 completed the study. This cohort represented the majority of all patients on antiretroviral (ARV) therapy in Oman. Antiretroviral drug adherence was measured over 6-month period using self-report and pill count measures. The aims of this study were to determine the degree of drug adherence among Omani patients on ARV therapy, to examine the relationship between adherence and virologic and immunologic outcomes, and to determine barriers to and predictors of adherence over time in HIV-infected patients. Antiretroviral adherence was not stable over time. However, the monthly variations in self-report adherence (SRA) and pill count adherence (PCA) were not statistically significant (p > 0.05). The study found that the mean adherence for the entire study period was 90% by SRA (range: 80.7% - 98.4%) and 87.6% by PCA (range: 84.4% - 92.5%). Fifty percent and 52.2% of our patients had excellent (>95%) adherence when measured by self-report and pill count respectively. A significant correlation was found for virologic and immunologic outcomes across categories of adherence. For both measurements, significant differences were observed between adherence and detectable and undetectable viral load (VL). Thus, among patients with poor PCA (<80%), 75% had detectable virus (virologic failure) compared to 21.4% of those with excellent adherence >95%). Similarly, among patients with poor SRA, 71.4% had virologic failure compared with 23.5% of patients with excellent adherence. In relation to immunologic outcomes, significant differences were observed with PCA only. Among patients with poor PCA, 50% had immunologic failure compared with only 14.3% of those with excellent adherence. The study assessed the influence of sex, age, duration of therapy, and baseline VL and CD4* cell count. None of these significantly influenced adherence to ARV treatment. Medication related factors and adherence were also assessed. Of the prescribed drugs, Combivir; which is a combination of zidovudine and lamivudine, was missed by the least number of patients compared with the single drugs; zidovudine, efaverinz and indinavir. The most common reasons for missing medication were side effects and running out of drugs followed by forgetting to take medication and being away from home. Measures aimed at improving ARV drug adherence need to overcome factors associated with poor adherence, and build on those that are associated with good adherence. These should include education regarding the importance of adherence to therapy, frequent assessment of patient drug adherence, and development and prescription of simpler antiretroviral regimens.