A low-carbohydrate diet, frequently used for treatment of reactive hypoglycemia, hypertriglyceridemia, and obesity may affect thyroid function. We studied the effects of replacing the deleted carbohydrate with either fat or protein in seven healthy young adults. Subjects were randomly assigned to receive seven days of each of two isocaloric liquid-formula, low-carbohydrate diets consecutively. One diet was high in polyunsaturated fat (HF), with 10%, 55%, and 35% of total calories derived from protein, fat, and carbohydrate, respectively. The other was high in protein (HP) with 35%, 30%, and 35% of total calories derived from protein, fat, and carbohydrate. Fasting blood samples were obtained at baseline and on day 8 of each diet. A meal tolerance test representative of each diet was given on day 7. The triiodothyronine (T3) declined more (P less than .05) following the HF diet than the HP diet (baseline 198 micrograms/dl, HP 138, HF 113). Thyroxine (T4) and reverse T3 (rT3) did not change significantly. Thyroid-stimulating hormone (TSH) declined equally after both diets. The insulin level was significantly higher 30 minutes after the HP meal (148 microU/ml) than after the HF meal (90 microU/ml). The two-hour glucose level for the HP meal was less, 85 mg/dl, than after the HF meal (103 mg/dl). Serum triglycerides decreased more after the HF diet (HF 52 mg/dl, HP 67 mg/dl). Apparent benefits of replacing carbohydrate with polyunsaturated fat rather than protein are less insulin response and less postpeak decrease in blood glucose and lower triglycerides. The significance of the lower T3 level is unknown.