Introduction rational drug use prevents wastage of resources, loss of confidence in healthcare system and drug-related morbidity and mortality. This study aims to assess drug use in Primary Health Centers (PHCs) in Lagos State, Nigeria using the World Health Organization in collaboration with the International Network of Rational Use of Drugs core drug use indicators. Methods the study was conducted between February to October 2021 as a comparative observational survey of selected PHCs. It included a retrospective and prospective cross-sectional design for prescribing and patient care indicators assessing 2640 prescriptions and clients respectively. Data were analyzed and presented as frequency with percentage or mean with standard deviation, as applicable. The performances of the types of PHCs were compared using two-sample t-test. A 2-tailed p-value < 0.05 was considered statistically significant. Results average number of drugs per prescription, drugs prescribed by the generic name, percentage of encounters with prescribed antibiotics and injections were 3.6 ± 0.9%, 76.5 ± 18.5%, 63.3 ± 19.1% and 21.1 ± 24.1% respectively with no significance difference between the comprehensive and basic PHCs. For all the facilities, the average consultation and dispensing times were 10.5 ± 6.0 minutes, 244.9 ± 179.2 seconds respectively. In this study, the percentage of patients’ knowledge of the correct dosage was 72.4 ± 38.3%. There is statistically significant difference in availability of key drugs in stock between the comprehensive and basic PHCs (p-value 0.0001). Conclusion irrational drug use practices exist in comprehensive and basic PHCs. There is a need to implement interventions aimed at strengthening good prescribing and patient-care practices across the PHCs in Lagos State.