The loss of lean body mass accompanying acquired immunodeficiency syndrome (AIDS)-associated cachexia is refractory to current modes of therapy. GH and insulin-like growth factor-I (IGF-I) stimulate protein accretion, but resistance to GH action has been reported in malnutrition and infection. We hypothesized that GH resistance occurs in AIDS-associated cachexia, but that treatment with IGF-I would be anabolic. A single injection of GH produced a smaller increase in circulating IGF-I in 21 patients with AIDS compared to that in 23 age-matched controls (141 +/- 15 vs. 194 +/- 15 micrograms/L; P < 0.02), indicating partial GH resistance. Ten subjects received either low or high dose iv recombinant IGF-I 12 h daily for 10 days. Cumulative nitrogen retention was positive for both dosage groups (low dose, 15.42 +/- 6.37 g; high dose, 3.62 +/- 4.15 g), but a significant increase in daily nitrogen retention occurred only in the low dose group on days 2, 4, 5, 6, and 7. Nitrogen balance and protein turnover (estimated by [13C]leucine and [15N] glycine kinetics) during the final 3 days of treatment were unchanged compared to baseline values, confirming the transient nature of the anabolic response. Repeated administration of IGF-I decreased IGF-binding protein-3 levels, producing lower intrainfusion levels of IGF-I and limiting its therapeutic efficacy. The basal metabolic rate increased with high dose IGF-I and may have contributed to the lack of anabolic effect. We conclude that partial GH resistance occurs in AIDS-associated cachexia. Treatment with low dose recombinant IGF-I produces significant, but transient, nitrogen retention. Alternate routes of IGF-I administration or coadministration with GH may prevent attenuation of IGF-I action.