This study examined the factors affecting adherence to antiretroviral therapy (ART) among HIV clients at Kabale Regional Referral Hospital, Kabale District. Adherence to ART is the single most important determinant of treatment success, yet suboptimal adherence remains a persistent challenge that undermines viral suppression and fuels drug resistance. The study investigated how patient-related factors, medication-related factors, health-system factors, and socioeconomic support relate to ART adherence. A cross-sectional survey design with a mixed-methods approach was adopted, and data were collected from 210 HIV clients on ART and 20 health workers using structured questionnaires and key-informant interviews. Descriptive statistics, Pearson correlation, and regression-based path analysis were used. The results revealed a strong positive and significant relationship between the identified factors and ART adherence (r = 0.67, p < 0.01), with the factors jointly explaining 65.0% of the variance in adherence (R² = 0.650). Patient-related and health-system factors emerged as the strongest predictors. The study concludes that improving patient support, health-system responsiveness, and socioeconomic conditions significantly enhances ART adherence and recommends adherence counselling, strengthened health-system support, and social support interventions.