ICU-acquired weakness (ICU-AW) is an acute diffuse muscle weakness that is an important prognostic factor for patients in today’s intensive care units. In this study, we created a novel ICU-AW model of sepsis in which septic rats were immobilized in a lower limb cast for 96 hours. We investigated the structural changes in muscle tissue following lipopolysaccharide (LPS)-induced inflammation and cast immobilization from a pathological viewpoint. Ten-week-old male rats were divided into four groups: control group (C-group, n=6), cast-immobilized group (CC-group, n=6), LPS administration group (L-group, n=6), and LPS administered and cast immobilized group (LC-group, n=6). The LPS administration time and dose were determined based on the results of a study experiment performed first. After the LPS administration/cast-immobilization experiment, body weights and wet weights of both isolated soleus muscles were measured. Muscle tissue was analyzed from a pathological perspective using optical and transmission electron microscopy. Although the comparison of body weights between the four groups showed no significant differences after 96 h, a severe loss of soleus muscle wet weight and decrease in the relative soleus weight ratio were observed in the LC-group. Optical microscopy results showed that a significant increase in cross-sectional area (CSA) and decrease in the average number of muscle fibers were observed in the LC-group compared with all other groups (p<0.05), and the CSA showed a mixture of small and large muscle fibers. The average number of vacuoles in muscle fibers appeared to be significantly increased in the CC and LC-groups (p<0.05, vs. the C, L-group). Longitudinal electron microscopic images showed distorted sarcomeres, Z-band disruption, and loss of actin-myosin filaments was present in the cross-sections. The present study suggested that from a pathological viewpoint, a combination of inflammation and immobilization causes more severe consequences in terms of structural changes in muscle tissue than either factor alone.