To determine whether a 48-week course of amprenavir-based antiretroviral therapy is associated with metabolic alterations, 14 clinically stable human immunodeficiency virus (HIV)-infected, protease inhibitor-naive adults initiated amprenavir-based triple therapy. Twelve subjects (86%) achieved HIV RNA levels of <400 copies/mL at week 24. Fasting glucose and insulin levels did not change. Insulin sensitivity did not decrease in the first 24 weeks, but a trend toward a decrease appeared at week 48. Six subjects experienced onset or worsening of glucose tolerance by week 24. Levels of fasting triglycerides and low-density lipoprotein, high-density lipoprotein, and total cholesterol increased. Bone mineral content, lean tissue, total fat, trunk fat, limb fat, and the ratio of trunk to limb fat increased at week 48. Amprenavir-based therapy was associated with increases in serum lipid levels but no short-term decrease in insulin sensitivity. A trend toward insulin resistance appeared late in the study following weight gain, particularly of trunk fat, but without loss of limb fat.