Muscle wasting, that is, reduction in muscle mass, is frequently observed in patients with chronic heart failure (CHF) and diabetes mellitus (DM). We retrospectively examined 185 patients with CHF (median age of 71 years [interquartile range, 61-78 years]; 64% male) who received a dual-energy X-ray absorptiometry scan for assessment of appendicular skeletal muscle mass index (ASMI). Seventy patients with CHF (38%) had DM. Patients with DM had higher prevalences of ischemic heart disease and hypertension, lower levels of estimated glomerular filtration rate (eGFR) and ASMI, and higher levels of plasma renin activity (PRA) than did patients without DM. In simple regression analyses, ASMI was positively correlated with the Mini Nutritional Assessment Short Form (MNA-SF) score and levels of hemoglobin, eGFR, and fasting plasma insulin and was negatively correlated with levels of N-terminal pro B-type natriuretic peptide, PRA, and cortisol. In multiple linear regression analyses, age, MNA-SF score, DM, fasting plasma insulin level, and PRA were independently associated with ASMI. When multiple linear regression analyses were separately performed in a non-DM group and a DM group, MNA-SF score and fasting plasma insulin level were independent variables for ASMI in both groups. PRA was independently associated with ASMI in the DM group but not in the non-DM group, whereas cortisol concentration was independently associated with ASMI only in the non-DM group. In addition to malnutrition and reduction in plasma insulin, renin-angiotensin system activation may be responsible for the development of muscle wasting in CHF patients with DM.