Background: Underweight chronic obstructive pulmonary disease (COPD) patients with involuntary weight loss have a poor prognosis; no effective therapy is currently available. We conducted the first clinical trial seeking to determine whether combination therapy with an appetite stimulant and an anabolic steroid would have beneficial effects on body composition for patients with COPD cachexia. Methods: We conducted a 12-week pilot study in which 4 men and 5 women (age 64±10 y, forced expiratory volume in 1 second [FEV₁] 31±9 %pred., body mass index [BMI] 18±3 kg/m²) with low-normal testosterone levels (average 532±45ng/dl in men and 12.4±5.3ng/dl in women) and weight loss ≥10 lbs over the previous year were treated with oral megestrol acetate 800mg/day plus weekly testosterone enanthate injections, initially 125 mg in men and 40 mg in women, with doses subsequently adjusted targeting circulating nadir testosterone levels of 850 and 300 ng/dl, respectively. Results: On treatment, nadir testosterone level increases averaged 160±250 ng/dl (NS) in men and 322±49 (p<0.001) ng/dl in women. Body weight increased in all individuals, with average end-intervention weight gain of 3.1±2.2 kg (p<0.005). Two women and 2 men had COPD exacerbations and did not complete the 12-week study. In the 5 individuals who completed, dual energy x ray absorptiometry (DEXA) scans revealed an average 2.0±1.5 kg lean mass and 2.3±1.7 kg fat mass increase (each p<0.05). No adverse effects of treatment were detected. Conclusions: Combination therapy reversed the trajectory of involuntary weight loss and increased lean mass in cachectic COPD patients. Though the interventions were apparently well tolerated, participant drop-out rate was high. Larger randomized placebo-controlled long-term studies with functional outcomes are needed.