Background: Persons with multiple sclerosis (MS) have many health conditions related to overweight and obesity, but little is known about how body composition among those with MS compares to those without MS at the same weight. Objective: To compare differences in whole body and regional body composition between persons with and without MS matched for sex and body mass index (BMI). Methods: Persons with MS (n = 51) and non-MS controls (n = 51) matched for sex and BMI. Total mass, lean mass, fat mass, and percent body fat (%BF) of total body and arm, leg, and trunk segments were assessed using dual-energy X-ray absorptiometry (DXA). Results: Men with MS had significantly less whole body lean mass (mean difference: 9933.5 ± 3123.1 g, p < 0.01) and higher fat mass (mean difference: 6079.0 ± 2137.4 g, p =.01) and %BF (mean difference: 9.43 ± 2.04%, p < 0.01) than BMI-matched non-MS counterparts. Further, men with MS had significantly lower lean mass in the arm (p = 0.02) and leg (p < 0.01) and higher fat mass in the arm (p = 0.01), leg (p = 0.03) and trunk (p = 0.03) than men without MS. Men with MS had significantly higher %BF in all three regions (p < 0.01) than men without MS. There were no differences between women with and without MS. Conclusions: We observed significant differences in whole body and regional body composition between BMI-matched men with and without MS. Additional research is needed to further explore differences in body composition, adipose distribution, and the impact of these differences on the health and function of men with MS.