The skeletal muscle and the immune system are heavily affected by the space environment. The crosstalk between these organs, although established, is not fully understood. This study determined the nature of immune cell changes in the murine skeletal muscle following (hindlimb) unloading combined with an acute session of irradiation (HLUR). Our findings show that 14 days of HLUR induces a significant increase of myeloid immune cell infiltration in skeletal muscle.