Plasma testosterone (T) and sex hormone binding globulin (SHBG) were assayed in normal controls (N = 9) and hypothyroid patients (N = 17) receiving increasing doses of L-T4 (0.2 mg, 0.4 mg for 30 days), followed first by 30 days without medication and then by 30 days each of 0.05 mg L-T3 and 0.2 mg L-T3. Normal male controls showed a significant increase in plasma T only at high doses of either L-T4 (0.4 mg) or L-T3 (0.2 mg). A small but significant increase in plasma T levels was observed in normal female subjects at 0.4 mg of T4. In both men and women, plasma SHBG increased in a dose-dependent manner with L-T4 or L-T3 and correlated positively and significantly with serum thyroid hormone levels. Hypothyroid male subjects had significantly lower levels of plasma T (mean +/- SD) of 279 +/- 131 ng/dl as compared with normal males (431 +/- 118 ng/dl), which reached the normal range only at a relatively high dose of either L-T4 (0.4 mg) or L-T3 (0.2 mg). No significant changes in plasma T were seen in the hypothyroid female group. Basal plasma SHBG levels were significantly lower in both hypothyroid men and women and increased towards normal levels during L-T4 and L-T3 therapy, although the response to thyroid hormones was significantly lower than that of normal controls. These results indicate that thyroid hormone therapy increases plasma SHBG levels in both normal and hypothyroid patients and that this increase precedes the expected elevation of plasma T in males.