Normalization of basal thyrotrophin (TSH) level is used as the endpoint in L-thyroxine (L-T4) therapy of primary hypothyroidism. However, several reports have questioned the reliability of this index because of seasonal variation of TSH. Therefore, we studied 85 consecutive patients with primary hypothyroidism over a period of 3.5 y. In these patients, TSH response (delta TSH) to intravenous thyrotrophin releasing hormone (TRH) administration was examined when basal TSH was normalized with L-T4 therapy. Eight patients showed a blunted response (delta TSH less than 5 microU), whereas 27 patients demonstrated an exaggerated response (delta TSH greater than 25 microU). Thus, 42% of patients were apparently on inappropriate L-T4 dosage. These abnormal TSH responses normalized on adjusting the L-T4 dosage alone; prolonged therapy with the same dose failed to normalize TSH responses. Minor seasonal variations of basal TSH were observed in 30% of patients. However, TSH response to TRH remained normal. Hence, no adjustment of L-thyroxine dose was required. This study, therefore, demonstrates that normalization of TSH response to TRH administration rather than basal TSH may be the best index of adequate L-thyroxine therapy in primary hypothyroidism.