There is an expanding body of research on exercise intervention for multidisciplinary rehabilitation of people with multiple sclerosis (PwMS). Most of this research focuses on people with mild/moderate MS who are ambulatory. As the costs of care increases with increasing disability, it is important to evaluate the evidence for interventions in nonambulatory PwMS. The aim of this study was to evaluate the evidence regarding physical rehabilitation interventions in nonambulatory PwMS. The databases AMED, CINAHL, MEDLINE, EMBASE and PSYCHARTICLES were searched up to 31 May 2011. Reference lists, Google Scholar and PEDro were also searched. Trials of physical rehabilitation interventions in nonambulatory PwMS that analysed nonambulatory results separately were included. Pharmacological, surgical, medical and assistive device interventions were excluded. Risk of bias was assessed and the GRADE approach was used to classify the quality of evidence. Sixteen low-grade studies, only three of which were randomized controlled trials (RCTs), were found. There are trends of improvement following some interventions such as cooling suits, respiratory training and multidisciplinary rehabilitation, but there is no high-grade evidence in terms of the benefits of interventions in this population. The effectiveness of physical rehabilitation interventions in nonambulatory PwMS remains unclear. Although trends in the results suggest positive benefits, conclusions cannot be drawn about the effectiveness of interventions in this population because of the small number and poor quality of studies. As approximately 25% of PwMS are nonambulatory and considerable costs are associated with their care, it is imperative that efforts be to increase the quality of evidence for nonambulatory PwMS.