To assess the clinical usefulness of serum pro-gastrin-releasing peptide (Pro-GRP) as a tumor marker for small cell lung carcinoma (SCLC), we measured serum levels of Pro-GRP with a newly developed ELISA and measured serum levels of neuron-specific enolase (NSE) in 44 patients with untreated SCLC and 77 patients with untreated non-SCLC. We prospectively measured serum levels of Pro-GRP and NSE in SCLC patients after initial treatment until relapse. The sensitivity (70%) and specificity (91%) of Pro-GRP were similar to those of NSE (70 and 86%). Thirty-nine % of patients who had a partial response still had elevated serum levels of Pro-GRP at the time of restaging after initial treatment. In follow-up study, 94% of patients had elevated serum levels of Pro-GRP again at the time of relapse, whereas 37% of patients showed elevated levels of NSE. Levels of Pro-GRP increased a median of 35 (-95 to 151) days before clinical evidence of relapse was detected with successive physical examinations and imaging studies, whereas levels of NSE increased 20 (-85 to 124) days after relapse was detected (P < 0.05). Pro-GRP was helpful as a diagnostic aid and a marker for therapeutic effect and relapse in patients with SCLC, supplemented to serum NSE.