ABSTRACT: Retention of male people who inject drugs (PWIDs) is a major challenge for harm reduction programs that include sterile needle/syringe exchange in resource-limited settings like Pakistan. We assessed the risk factors for loss to follow-up among male PWIDs enrolled in a risk reduction program in Karachi, Pakistan.We conducted a prospective cohort study among 636 HIV-uninfected male PWIDs enrolled during March-June 2009 in a harm reduction program for the estimation of incidence rate. At 24 months post-enrollment, clients who had dropped out of the program were defined as lost to follow-up and included as cases for case-cohort study.The median age of the participants was 29 years (interquartile range: 23-36). Active outreach accounted for 76% (483/636) of cohort recruits. Loss to follow-up at 24 months was 25.5% (162/636). In multivariable logistic regression, younger age (AOR: 0.97, 95% CI: 0.92-0.99, p = 0.028), clients from other provinces than Sindh (AOR: 1.49, 95% CI: 1.01-2.22, p = 0.046), having no formal education (AOR: 3.44, 95% CI: 2.35-4.90, p<0.001), a history of incarceration (AOR: 1.68, 95% CI: 1.14-2.46, p<0.008), and being homeless (AOR: 1.47, 95% CI: 1.00-2.19, p<0.049) were associated with loss to follow-up.Our cohort retained 74.5% of male PWIDs in Karachi for 24 months. Its loss to follow up rate suggested substantial ongoing programmatic challenges. Programmatic enhancements are needed for the highest risk male PWIDs, i.e., younger men, men not from Sindh Province, men who are poorly educated, formerly incarcerated, and/or homeless.