Background: Persons who inject drugs (PWID) are at increased risk of HIV and HCV infection through the use of blood contaminated syringes and paraphernalia. Obtaining illicit drugs in prefilled syringes might appeal to some PWID for convenience or necessity, yet this practice could lead to infections and drug overdose since syringe hygiene and drug concentrations cannot be known. Objectives: This dissertation research sought to characterize prefilled syringe use, estimate their prevalence and incidence, and identify factors associated with their use. It also sought to elucidate practices and motivations behind prefilled syringe use among PWID in San Diego, California. Methods: This dissertation is comprised of three studies assessing different aspects of prefilled syringe use among PWID enrolled in a longitudinal cohort study. Study one was a cross-sectional logistic regression analysis of baseline data from 574 PWID to determine the prevalence and correlates of ever using prefilled syringes. Study two was a qualitative study of 25 PWID, 10 of whom reported using prefilled syringes to describe contextual factors that influence their use. Study three included data from three study visits and used GEE to determine factors associated with prefilled syringe use in the last 6 months. Results: For Study one, participants were predominately white (50.9%) males (73.9%) with a mean age of 43.4 years (range 18-80); 33.3% reported ever using prefilled syringes. PFSU was independently associated with ever having a rushed injection due to police presence, ever being in prison, injecting most often in public versus private places, ever overdosing on opioids, and injecting drugs in Mexico. A number of themes emerged during the interviews conducted for study two, including: 1) unknown contents; 2) trust; 3) pressure to inject quickly; and 4) disease transmission risk. Study three found participants who reported PFSU in the last 6 months were more likely to report an overdose, sharing other injection paraphernalia, being homeless, and to report using the syringe exchange program, all in the last 6 months. Conclusion: HIV, HCV, and overdose interventions should focus on factors that influence risky behaviors and be targeted towards individuals who face the greatest barriers to safe injection such as limited access to clean syringes and homelessness.