Availability and accessibility of essential medicines for HIV recipients of care varies across regions in Nigeria. This study seeks to compare access and availability of medicines for HIV in the South south and Northeast regions of Nigeria. Data were collected from 120 health facilities and 385 respondents using structured questionnaires and analysed using descriptive statistics and thematic analysis. The study methodology included an exploratory sequential mixed of quantitative and qualitative methods, including facility assessments, in-depth interviews, client satisfactory questionnaire conducted amongst HIV program stakeholders and HIV recipients of care. The study found that the HIV program in the regions have made progress in improving the accessibility of essential medicines for HIV patients. The North-East had an average access rate of 87.1%, while the South-South had a slightly higher average access rate of 85.6%. The North-East had a prescription rate of 100% for antiretroviral therapy (ART) for adolescents and for the preventive treatment for tuberculosis (INH + Pyridoxine). On the other hand, access to micronutrient supplementation was higher in the South-South region at 94.7%, compared to the North-East region with a rate of 74.2%. In conclusion, this study highlights that the availability of essential medicines such as ART drugs, micronutrients and prophylaxis for opportunistic infections, medicine supply, storage and documentation has improved overtime with support from donor agencies, though still challenged with electronic management systems and need for adequate procurement, quantification, additional technical assistance, funding and supply chain infrastructure is recommended to be addressed towards achievement of HIV epidemic control in Nigeria. Keywords: Essential medicines, Health systems, HIV, North-East, South-South.