A study of 61 patients with small cell carcinoma of the lung using specific RIAs for 2 human neurophysins (HNPs) has revealed that plasma levels of 1 or both HNPs are substantially elevated (> 3 times) in 62% of the patients before the commencement of therapy. These elevated HNPs may be a consequence of production/release by tumor. Eighteen patients with elevated plasma HNPs and 14 with normal values were followed during therapy. All of the patients with normal pre-therapy levels maintained these normal levels regardless of the course of their disease. For all patients with elevated HNP levels before therapy, there was good agreement between changes in these elevated values and clinically assessed responses. Partial or complete remission (12 patients) was associated with a 2- to 30-fold reduction in HNP levels, progressive disease (6 patients) was associated with a rise in HNP levels, and relapse after a previous objective response (6 patients) was associated with an increase in plasma HNPs over values found during remission. For many of the patients in clinical remission, HNPs remained elevated above normal values, and RIA data seem to forecast recurrent disease several weeks before clinical recognition. These data provide good evidence that our RIAs for HNPs can provide a valuable guide to therapeutic management of small cell carcinoma of the lung.