Uncontrolled studies show fatigue, anorexia, depression, and mortality are associated with low testosterone in men with cancer. Testosterone replacement improves quality of life and diminishes fatigue in patients with non-cancer conditions. The primary objective was to evaluate the effect of testosterone replacement on fatigue in hypogonadal males with advanced cancer, by the Functional Assessment of Chronic Illness Therapy-Fatigue subscale (FACIT-Fatigue) at day 29. This is a randomized, double-blinded placebo-controlled trial. Outpatients with advanced cancer, bioavailable testosterone (BT)3/10 on the Edmonton Symptom Assessment Scale were eligible. Intra-muscular testosterone or sesame seed oil placebo was administered every 14 days to achieve BT levels 70-270 ng/dL. Sixteen placebo and 13 testosterone-treated subjects were evaluable. No statistically significant difference was found for FACIT-fatigue scores between arms (-2 +/- 12 for placebo, 4 +/- 8 for testosterone, p = 0.11). Sexual Desire Inventory score (p = 0.054) and performance status (p = 0.02) improved in the testosterone group. Fatigue subscale scores were significantly better (p = 0.03) in those treated with testosterone by day 72. Four weeks of intramuscular testosterone replacement in hypogonadal male patients with advanced cancer did not significantly improve quality of life. Larger studies of longer duration are warranted.