Since 2005, California law allowed over-the-counter (OTC) syringe sales pending local authorization. Although pharmacy sales of OTC syringes are associated with reduced injection-mediated risks and decreases in human immunodeficiency virus infection rates, little is known about the factors associated with syringe purchase among injection drug users (IDUs). Using a cross-sectional design, the authors applied targeted sampling to collect quantitative survey data from IDUs (n = 563) recruited in San Francisco, California, during 2008. They also compiled a comprehensive list of retail pharmacies, their location, and whether they sell OTC syringes. They used a novel combination of geographic information system and statistical analyses to determine the demographic, behavioral, and spatial factors associated with OTC syringe purchase by IDUs. In multivariate analyses, age, race, injection frequency, the type of drug injected, and the source of syringe supply were independently associated with OTC syringe purchases. Notably, the prevalence of OTC syringe purchase was 53% lower among African-American IDUs (adjusted prevalence ratio = 0.47, 95% confidence interval: 0.33, 0.67) and higher among injectors of methamphetamine (adjusted prevalence ratio = 1.35, 95% confidence interval: 1.07, 1.70). Two neighborhoods with high densities of IDUs had limited access to OTC syringes. Increased access to OTC syringes would potentially prevent blood-borne infectious diseases among IDUs.