The need for quarterly clinic visits is a barrier to use of subcutaneous depot medroxyprogesterone acetate (DMPA-SC) contraception. The ability to self-inject at home may enhance method acceptance. Since efficacy depends on proper administration, we evaluated whether women could correctly perform simulated injections of DMPA-SC in a Uniject™ injection system using printed Instructions for Use (IFU), with and without hands-on training. Adult female volunteers (N=120) injected DMPA-SC into a rubber trainer at two visits, 3 months apart. Women were randomly assigned to receive hands-on training before the first injection or no training. The primary outcome was the proportion of women who successfully operated the injection system. An attempt was defined as successful if the participant correctly performed all critical steps in the injection procedure (getting ready, selecting an injection area, preparing the injector, mixing the medicine, activating the injector, injecting the dose) and expelled the dose without unexpected interruption. The success rate at month 3 was considered the primary endpoint. A one-sided 95% confidence limit >80% was used to declare the delivery system and IFU “fit for purpose.” With training, the success rate (one-sided 95% confidence limit) was 90.0% (81.8%) at day 1 and 96.7% (90.4%) at month 3; without training, rates were 76.7% (66.7%) and 88.3% (79.8%), respectively. The trained (96.4%) and untrained (92.2%) groups successfully completed injecting into the trainer at first injection, the final critical step of the injection procedure, despite the fact that about one third of participants considered expelling depot medroxyprogesterone acetate (one component of this step) to be difficult. Most participants understood the IFU and successfully operated the injection system. Initial hands-on training improved success rates at both visits. For women interested in self-injection, providers should review all steps of the IFU, provide a demonstration, supervise initial injection(s) and ensure that the patient is aware of future injection dates. The potential for self-injection to improve adherence should be studied. After initial training, women performed simulated self-injections of DMPA-SC in the Uniject system proficiently using printed instructions. Women who are motivated and demonstrate competent injection technique during training can be relied upon to self-inject correctly at home. DMPA-SC users not suitable for self-injection should continue receiving injections at the clinic.