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Objective: The objective of the study was to review the evidence for the effectiveness of telephone psychotherapy on psychological outcomes in people with multiple sclerosis (MS). Method: We conducted a systematic search of EMBASE, PsycINFO, PsycARTICLES, MEDLINE, CINAHL, Web of Science, and hand-searched relevant journals to identify randomized controlled trials (RCTs) that evaluated the effectiveness of telephone psychotherapy on psychological outcomes in people with MS (last search completed on October 1, 2015). The methodological quality of each included trial was assessed, based on a standardized list of methodological criteria. Where available, data were extracted and combined in a meta-analysis to compute effect size estimates. Results: Eleven RCTs and 1,104 participants were identified. The meta-analysis found a moderate effect of the intervention on depression (SMD 0.47 [95% confidence interval 0.21–0.73]). The meta-analysis also found small to moderate short-term effects of the intervention on fatigue, quality of life, MS symptoms, physical activity, and medication adherence, compared with controls and other interventions. RCT designs were heterogeneous. All studies had at least 1 high or unclear risk of bias. Conclusions: Telephone psychotherapy provides small and moderate benefits in depression, fatigue, quality of life, MS symptoms, physical activity, and medication adherence in the short term. Few gains were sustained in the long term. Studies of better quality are needed.