IntroductionAdherence to Option B+ antiretroviral medication (ART) is essential for the successful implementation of the Prevention of Mother-to-Child Transmission (PMTCT) program. However, poor adherence to Option B+ PMTCT drugs among women results in increased viral load and mother-to-child transmission and reduces immunological and clinical outcomes. ObjectiveThe objective of the study was to assess the level of Option B plus drug adherence for preventing mother-to-child transmission of HIV and associated factors among HIV positive women in selected government health facilities of Awi zone, Amhara region, Northwest Ethiopia,2020. MethodsThis institutional-based cross-sectional study was conducted from March 1 to April 30 among 358 HIV-positive women (pregnant and lactating mothers). A multistage sampling procedure was used to select the study participants. Data were collected using a structured questionnaire through interviews. The collected data were entered into EPI Data 3.1 statistical software for data management and analyzed using SPSS version 25 statistical package. The associations between variables were analyzed using bivariate and multivariable logistic regression models. A p-value ≤ 0.05 at the 95% confidence interval was considered statistically significant. ResultsOut of the 358 participants, adherence to Option B+ PMTCT was 83.24%. The study revealed that counselling [AOR=4.4, 95% CI: 1.60-12.29], partner support involvement [AOR=3.0, 95% CI: 1.17-7.92], and time taken to reach from home to the facility [AOR=3.1, 95% CI: 1.51-6.52] were significantly associated with the level of adherence to Option B+ PMTCT. ConclusionThis study showed that the level of Option B+ PMTCT drug adherence was lower than the nationally recommended adherence level. Good counselling, partner support, and reduced travel time from home to the facility were associated with adherence to Option B+ PMTCT drugs. Therefore, counselling is crucial for increasing adherence to Option B+ PMTCT drugs. Accessible health facilities reduce travel burdens, encourage regular clinic visits, and enhance adherence to PMTCT drugs. Partners can provide reminders, attend appointments, offer emotional support, and explore alternatives such as mobile clinics or medication delivery services.