Objective: Rituximab is used as an off-label treatment for relapsing-remitting multiple sclerosis (RRMS); however, the comparative efficacy and safety of rituximab versus currently licensed disease-modifying drugs (DMDs) for RRMS is unknown. A systematic literature review was conducted to evaluate the available data pertaining to efficacy and safety of rituximab in adult patients with RRMS and highly active relapsing multiple sclerosis (HA-RMS); data quality was critically assessed via risk of bias (RoB) assessment. Methods: Biomedical literature databases were searched until mid-2018 and key proceedings were searched from 2016 to 2018. Critical appraisal of non-randomized studies was conducted using the Cochrane RoB assessment tool; randomized controlled trials (RCTs) were appraised using comprehensive assessment criteria based on the NICE guidelines. Results: Thirty-eight unique studies based on 49 publications were identified: 25 RRMS studies (one RCT) and 13 HA-RMS studies (no RCTs). The evidence among patients with RRMS generally favored rituximab in comparison to placebo (relapse rate) and interferons/glatiramer acetate (relapse rate and disability progression), although much of the non-randomized data were descriptive and/or not statistically significant. In comparison to placebo, rituximab was associated with a greater risk of adverse events. Two-thirds of the non-randomized RRMS studies were associated with critical/serious RoB; the single RCT was associated with low RoB. Furthermore, all of the non-randomized HA-RMS studies were associated with critical/serious RoB. Conclusions: Available evidence of off-label rituximab use for the treatment of patients with RRMS suggests generally favorable efficacy versus placebo and interferons/glatiramer acetate; however, the poor quality of the included studies limits any robust conclusions.