To assess efficacy, safety, and subject satisfaction with a new, low dose subcutaneous formulation of depot medroxyprogesterone acetate (DMPA-SC) contraceptive administered every 3 months (12–13 weeks). Two phase 3, open-label, noncomparator, multinational, multicenter 1-year studies were conducted; 1 in the Americas, the other in Europe and Asia. Sexually active, regularly menstruating women 18–49 years of age received DMPA-SC (104 mg) injection at 0, 13, 26, and 39 weeks. Subjects receiving ≥1 dose of study medication constituted the intent-to-treat (ITT) population. Subjects that successfully self-injected in the office were given the option of home self-injection for injections 3 and 4. Treatment failure cumulative pregnancy rate at 1 year was the primary endpoint. Safety endpoints included incidence of amenorrhea, irregular bleeding, and adverse events. Satisfaction with treatment was evaluated through a Patient Satisfaction Questionnaire (PSQ) at injection visit, weeks 25–27, and weeks 51–53, and an End of Treatment Questionnaire (EOTQ). The ITT population consisted of 722 and 1065 subjects in the Americas and European/Asian trials, respectively (BMI range, 14.7–57.7 kg/m2). None of the subjects in either trial became pregnant during 16,023 woman-cycles of exposure to DMPA-SC, excluding months in which barrier contraception was used at least sometimes or no intercourse occurred. Efficacy was independent of BMI or administrator. In both studies combined, no pregnancies were observed in overweight (BMI >25 to 30 kg/m2, 22.9%) or obese (BMI >30 kg/m2, 10.8%) subjects or in the 15.6% of subjects performing ≥1 home self-injection. A very high level of satisfaction with DMPA-SC was indicated in 3 PSQ and EOTQ measures: preferring it to other contraceptive methods, willingness to continue treatment and willingness to recommend it to a friend. The largest percentage (49.8%) of respondents indicated they would prefer home self-injection to injection by clinician (29.3%) or self-injection at the doctor's office (20.9%). Overall, DMPA-SC was well tolerated. Of the 1343 subjects assessed at month 12, most (63.7%) either lost or gained weight within a narrow range (-2.2 kg to +2.3 kg). Median weight change at month 12 was 1.7 kg (mean change, 1.7 kg) in the Americas trial and 1.0 kg (mean change, 1.4 kg) in the European/Asian trial. Most irregular bleeding decreased with time, whereas incidence of amenorrhea increased to 55% at month 12. Treatment-related side effects leading to discontinuation were reported in 8.8% of subjects. These studies show new DMPA-SC (104 mg every 12–13 weeks) contraceptive is highly effective and well tolerated, with efficacy uncompromised by BMI or administrator. Subjects reported a high level of satisfaction with DMPA-SC; in addition, more than 70% of subjects preferred the option of self-injection to injection by the clinician.