During the last 10 years there has been an increasing interest in studying the coexistence of osteoporosis and depression in the male population, due to the increased morbidity and mortality in the patients' life. The present retrospective study evaluates the effect of major depression on the bone density of Greek middle-aged men. By using the method of dual-energy X-rays absorptiometry (DEXA) we reviewed the bone mineral density (BMD) studies performed in the lumbar spine (LS) and/or femoral neck, in 97 men of the white race, aged 55 years with mean age±standard deviation (SD)= 65±10.6 years, and body mass index (BMI) 30.2±4. The patients were divided in two groups, based on the coexistence (Group A) or absence of major depression (Group B). In group A men, the incidence of osteoporosis was 34.8% and osteopenia 39.5%, while in group B the corresponding percentages were 9.3% and 42.6%. Statistically significant difference was observed in mean BMD between Group A (0.876±0.170) and Group B (0.961±0.136) at the level of P=0.008, and also in mean T score (-1.72±1.57 versus -1.06±1.17) at the level of P value: 0.02 in both groups, while the diagnosis of osteoporosis between the two groups was statistically significantly different too (P=0.001. Pearson R: 0.3, P=0.004). Furthermore, the model of multiple linear regression and ANOVA table revealed statistically significantly depression of 0.252 and 0.575 units in mean BMD value and mean T score respectively in man with major depression in comparison to a mentally healthy man of the same age and BMI (regression coefficient b, P< 0.02). In conclusion, we observed statistically significant difference in mean BMD and mean T score values between major depression and mentally healthy men. Moreover, almost triple relative risk for the development of osteoporosis was shown in men with depression as compared to mentally healthy men (RR: 3.8, P=0.02). Cortisone intake, hypertension and smoking were statistically independent factors for male depression and BMD. The clarification of the underlying interactive mechanism between major depression, sympathetic system activation, age and bone resorption is important.