Treatment with disease-modifying immunomodulators is recommended for patients with relapsing-remitting MS (RRMS). However, continuous adherence to treatment with these injected therapies can be challenging. The main objective was to examine the predictors of adherence to glatiramer acetate using a study model derived from Prochaska's transtheoretical model of change. We conducted a 12-week, prospective, observational study. Potential predictors included readiness stage, MS self-efficacy, decisional balance (pros and cons of self-injection), and injection competence. Adults with RRMS, either treatment-naïve (TN) or treatment-experienced (TE), taking glatiramer acetate for the first time were studied. Interventions (including injection training) were implemented to promote adherence. The evaluable population included 146 TN patients and 88 TE patients who had previously discontinued beta-interferons. Adherence rates did not differ between TN and TE groups (86% for both at week 12); however, predictors of adherence did. For TN patients, greater functional self-efficacy, higher self-injection competence at baseline, and improvement in self-injection competence over the first month of therapy predicted adherence. For TE patients, lower body mass index and longer duration of MS predicted adherence. Interventions to improve self-efficacy and self-injection competence should be a priority when treating TN patients. Behavioral predictors of adherence in TE patients warrant further study.