Clinical tumor specimens and cultures of small cell lung cancer (SCLC) produce 10- to 100-fold higher quantities of the BB isoenzyme of creatine kinase (CK-BB) (EC 2.7.3.2) than did other types of lung cancer. Serum CK-BB levels were evaluated in 105 newly diagnosed, previously untreated patients with SCLC. All patients were thoroughly staged, including 42 patients with limited-stage and 63 patients with extensive-stage disease. Serum CK-BB was elevated (greater than 10 ng/ml) in 27 patients (26%) (range, 11 to 522 ng/ml; median, 40 ng/ml). Only 1 of 42 patients with limited disease had an elevated serum CK-BB, while 26 of 63 (41%) of patients with extensive disease did. When patients were subgrouped according to the number of metastatic sites detected in pretreatment staging, a significant association between the presence of an elevated serum CK-BB and the number of metastatic sites was observed (p less than 0.005). No association between the presence of metastatic disease in a specific site and an elevated serum CK-BB could be detected. After adjusting for the number of metastatic sites, survival among patients with a normal pretreatment CK-BB was significantly better than in patients with an elevated CK-BB (p = 0.014). Sequential serum CK-BB determinations in 33 patients revealed an excellent correlation between clinical response to therapy and serum CK-BB levels. Continuous SCLC cell lines established from 13 patients in this study all expressed high levels of CK-BB. These data suggest that serum CK-BB determinations may be of value in estimating the extent of tumor dissemination, assigning prognosis, and monitoring response to therapy in patients with SCLC.