This study sought to determine the effects of recombinant human growth hormone (rhGH) treatment on aerobic capacity and functional status, and the physiological mechanisms thereof, in patients with human immunodeficiency virus (HIV)-associated wasting, using clinical exercise testing. Twenty-seven HIV-infected men with unintentional weight loss (≥10%), despite antiretroviral therapy, received rhGH (6mg·day-1) in a randomized placebo-controlled cross-over trial. Following three months of rhGH treatment, effort-independent ventilatory threshold (VeT) significantly improved (mean +/- SEM: 17.6 +/- 3.7%, P < 0.001) and six-minute walk test (6MWT) distance and work increased by 24.9 +/- 9.7m ( P = 0.068) and 33.3 +/- 8.8kJ (P < 0.001), respectively. Improvements in VeT and 6MWT work were correlated to rhGH treatment-induced increases in lean body mass. In a subgroup of 12 patients, one month of rhGH treatment significantly improved arteriovenous oxygen content difference (17.1 +/- 8.9%, P = 0.039) at a constant work rate. In conclusion, rhGH treatment-induced anabolism and increase in muscle oxygen extraction-utilization contribute to enhanced exercise performance in patients with HIV-associated wasting.