The intention of this study was to determine prevalence and associated factors with adherence to highly active ART among people living with HIV/AIDS (PLWHA) at the Debrebrihan Referral Hospital and Health Center, Northeast Ethiopia. A cross-sectional study design with systematic random sampling was conducted using a structured adherence questionnaire among 422 respondents from the hospital. Adherence was defined as not missing a single ART dose during the 30-day period prior to filling out the self-report. Among the participants, 95.5% were taking their medication without missing a dose. Factors such as having emotional or practical support positively encouraged ART adherence. However, users of traditional, complementary, and alternative medicine (TCAM) had a nearly five times higher risk for ART nonadherence (p = 0.05) than those not using TCAM. Strengthening emotional and practical support for PLWHA and integrating TCAM with the proper use of ART are vital to enhance ART adherence.