Background: In Iran, nonprescription (ie, over-the-counter [OTC]) and prescription- only drugs are available at pharmacies. Self-medication and self-prescription practices are widespread. Objective: The aim of this study was to assess self-medication and self-prescription practices in Iran, with an emphasis on determining the extent to which prescription-only drugs are obtained without a prescription and dzaracterizing those who engage in this practice. Methods: This observational, cross-sectional study was conducted at pharmacies in Isfahan, Iran, between August 2001 and March 2002. The pharmacies were randomly selected from clusters categorized by the number of prescriptions handled or claims submitted to a major insurance company. Drug requesters were categorized accordingly: those who requested drugs with a prescription and those who requested drugs without a prescription. Prescription-only and nonprescription drug items requested at pharmacies were identified and included in the analysis. Cluster sampling was used to determine sample size and also to ensure that the results were reflective of the population studied. In addition, questionnaires were completed by persons who were seeking drugs without a prescription. Observations were also carried out in each pharmacy. To ensure measurement reliability, we conducted a pilot study before the commencement of this study. We determined sample size based on a >90% power to detect change. Results: Fifty pharmacies were selected for inclusion in the study. A total of 33,282 drug items were identified on prescriptions presented at the pharmacies. This number served as sample size for this study. Of this number, 10,101 items were requested without a prescription, of which 9653 items (95.6%) were available and dispensed. Of the items dispensed, 5504 (57.0%) were prescription items. The percentage of prescription-only drugs sold without prescription to total pharmacy sales was 21.9%, 22.8%, 19.5%, and 10.7% in pharmacies with the fewest to the largest (<500, 500–999, 1000–1499, ≥1500) number of prescriptions, respectively. Individuals requesting OTC and prescription-only drugs without presenting a prescription used 1 of 3 behaviors: (1) verbal request (85.0%); (2) presenting the empty box, blister pack, or a sample of the drug (12.1%); or (3) showing a piece of paper (which was not a prescription) bearing the name of the drug (2.9%). The percentage of those with medical insurance who sought a drug without a prescription was significantly greater than the percentage of those who did not have medical insurance (61.6% [663] vs 38.4% [413], respectively; P < 0.001). Conclusions: The common practice of requesting and obtaining prescription-only drugs without a prescription in Iran, especially among persons with medical insurance, warrants research to identify the motives for this behavior and to improve the enforcement of existing laws regarding the dispensing of prescription-only drugs.