Objective. Examine the impact of comorbid depression on adherence to disease-modifying therapy (DMT) for multiple sclerosis (MS). Methods. A retrospective database was used to identify patients with MS treated with a DMT. Patients with MS and comorbid depression were matched to patients with MS only. Adherence to DMT was proxied by the medication possession ratio (MPR) and multivariate regressions were used to examine the association between comorbid depression and adherence to DMT. Results. Patients with comorbid depression had a 10 point lower MPR (P < 0.01) and were less likely to achieve a MPR of at least 80% (odds ratio (OR) = 0.55; 95% confidence interval (CI) 0.42-0.74) than those without depression. While treatment with an antidepressant generally had no significant impact on the likelihood of achieving an MPR threshold of 80% (OR = 1.32; 95% CI 0.50-3.48), adherence to antidepressant therapy guidelines were associated with improved adherence to DMT therapy. Conclusions. MS patients with comorbid depression were approximately half as likely to be adherent to their DMT relative to patients with MS without depression. Although treatment with antidepressant therapy generally did not improve the likelihood of adherence, treatment with antidepressants for at least 6 months was associated with better adherence to DMT.