Plasma human neurophysins (HNPs) were evaluated as tumor markers for patients with small cell carcinoma of the lung (SCCL) who were entered on limited disease and extensive disease treatment trials conducted by Cancer and Acute Leukemia Group B (CALGB). HNP values obtained before treatment showed 44% of tumors secreting vasopressin-associated HNP (VP-HNP), 14% secreting oxytocin-associated HNP (OT-HNP), and 11% producing both HNPs. There was a significantly higher incidence of HNP-secreting tumors for patients with extensive disease and two or more metastatic lesions than for patients with limited disease. There were no clear differences in response to treatment or in survival between patients with HNP-secreting tumors and those with nonsecreting tumors. Response to treatment evaluated by the change in plasma HNP, gave a 91% agreement with independently derived clinical impressions. Our data indicates that HNP evaluations provide sufficient sensitivity to forecast clinical response when it cannot be clearly assessed by conventional methods.