The effect of a disrupted immune system on the neuromuscular system is poorly characterized. We compared the strength and fatigue of RAG2(-/-) mice, which lack T-cells and B-cells, with immune intact controls. RAG2(-/-) mice demonstrated fatigue with shorter inverted hang-times (HT) and voluntary wheel-running (VWR) distance and total run times; they increased body weight more slowly but had proportionally normal forelimb grip strength (FGS) and VWR speed. Medial rectus femoris histopathology showed no change in fiber type proportions, no variation in type 2b fiber diameter, and no change in the percentage of central nuclei. There was no change in serum creatine kinase (CK) levels. Thus, in RAG2(-/-) mice body weight and fatigue were directly affected by a hypoactive immune system. Whether these effects were centrally or peripherally mediated is unknown. This model may help to explain fatigue in human conditions in which the immune system is suppressed or absent.