Context: This study examined the extent to which patient and trial characteristics moderate the effects of exercise on depressive symptoms among people with multiple sclerosis. Evidence acquisition: Twenty-four effects were derived from 14 articles published before August 2016 located using Google Scholar, MEDLINE, PsycINFO, PubMed, and Web of Science. Trials involved 624 people with multiple sclerosis and included both randomization to exercise training or a non-exercise control condition and measurement of depressive symptoms at baseline and at mid- and/or post-intervention. Hedges' d effect sizes were computed, study quality was assessed, and random effects models were used for all analyses. Meta-regression quantified the extent to which patient and trial characteristics moderated the estimated population effect. Analyses were completed in September 2016 and updated in February 2017. Evidence synthesis: Exercise training significantly reduced depressive symptoms by a heterogeneous mean effect Δ of 0.55 (95% CI=0.31, 0.78, p<0.001). Significant improvement in fatigue moderated the overall effect (β=0.37, p≤0.03). Significantly larger antidepressant effects resulted from trials in which exercise significantly improved fatigue (Δ=1.04, 95% CI=0.53, 1.55, k=8) compared with no significant improvement in fatigue (Δ=0.41, 95% CI=0.21, 0.60, k=14, z=2.91, p≤0.004). Conclusions: Exercise significantly improves depressive symptoms among people with multiple sclerosis. Exercise-induced improvements in fatigue significantly moderated exercise effects on depressive symptoms. Future trials may benefit from focusing on using exercise to concurrently improve depressive symptoms and fatigue as a symptom cluster.