To investigate the feasibility and safety of cardiopulmonary exercise testing (CPET) in patients with multiple sclerosis (MS). PubMed, EMBASE, CINAHL, SPORTDiscus, PsycINFO, ERIC, and the Psychology and Behavioral Sciences Collection were searched up to October 2014. References from retrieved articles were examined to identify additional relevant studies. Inclusion of original studies was on the basis of performance of maximal CPET, description of the protocol, and participants with definite MS aged ≥18 years. No language restrictions were applied. The quality of CPET reporting in included studies was scored according to a structured checklist considering 10 feasibility (eg, test abnormalities) and 12 safety quality criteria (eg, adverse events). Structured data extraction was performed for these feasibility and safety features of CPET. Forty-six studies were included, comprising 1483 patients with MS, with a mean age ± SD of 42.0±5.8 years and a median Expanded Disability Status Scale (EDSS) score of 2.8 (first quartile=2.1; third quartile=3.9; range of average EDSS scores, .75-5.8). Quality of reporting on CPET varied from 3 to 13 out of a possible 22 quality points. The percentage of test abnormalities (feasibility) was 10.0%, primarily because of an inability to maintain pedaling at a specific resistance. The percentage of adverse events (safety) was 2.1%. All adverse events were temporary. Based on the available data, we conclude that CPET is feasible provided that the CPET modality is tailored to the physical abilities of the patient. Furthermore, CPET is safe when recommended precautions and safety measures are implemented. However, future optimization of CPET will require protocolized testing and the implementation of standard reporting procedures. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.