Metabolic and hormonal modifications after long-term testosterone (T) treatment have never been investigated. 20 hypogonadal men (mean T = 241 ng/dL-8.3 nmol/L) with metabolic syndrome (MS, mean age 58) were treated with T-undecanoate injections every 12 weeks for 60 months. 20 matched subjects in whom T was unaccepted or contraindicated served as controls. Primary endpoints were variations from baseline of metabolic and hormonal parameters. In T-group, significant reductions in waist circumference (-9.6 ± 3.8 cm, P < 0.0001), body weight (-15 ± 2.8 Kg, P < 0.0001), and glycosylated hemoglobin (-1.6 ± 0.5%, P < 0.0001) occurred, along with improvements in insulin sensitivity (HOMA-I; -2.8 ± 0.6, P < 0.0001), lipid profile (total/HDL-cholesterol ratio -2.9 ± 1.5, P < 0.0001), systolic and diastolic blood pressure (-23 ± 10 and -16 ± 8 mm Hg, P < 0.0001, resp.), and neck and lumbar T-scores (+0.5 ± 0.15 gr/cm(2), P < 0.0001; +0.7 ± 0.8, P < 0.0001, resp.). Also, serum vitamin D (+14.0 ± 1.3 ng/mL, P < 0.01), TSH (- 0.9 ± 0.3 mUI/mL, P < 0.01), GH (0.74 ± 0.2 ng/mL, P < 0.0001), and IGF1 (105 ± 11 ng/mL, P < 0.01) levels changed in T-group but not in controls. Normalization of T levels in men with MS improved obesity, glycemic control, blood pressure, lipid profile, and bone mineral density compared with controls. Amelioration in hormonal parameters, that is, vitamin D, growth hormone, and thyrotropin plasma levels, were reported.