Acquired multidrug resistance is a major obstacle to a cure for small cell lung cancer (SCLC). Overexpression of the MDR1 gene occurs infrequently in multidrug-resistant SCLC cell lines. The multidrug resistance protein (MRP) can confer multidrug resistance, but its role in clinically acquired drug resistance is unknown. The purpose of this study was to measure expression of MRP and MDR1 mRNA in cell lines and clinical samples from SCLC patients and to correlate the results with drug sensitivity profiles. Twenty-three SCLC cell lines and 10 tumor samples from SCLC patients were examined. Samples expressing MRP and MDR1 were identified by reverse transcription-PCR, and levels of MRP mRNA in the cell lines were measured by quantitative reverse transcription-PCR. One of 23 cell lines (4%) expressed MDR1 mRNA, whereas MRP expression was detected in 19 of 23 cell lines (83%). There was a significant correlation between doxorubicin resistance and MRP expression levels (r = 0.422; P = 0.045). Of the 10 clinical samples, 3 expressed only MRP, 2 expressed only MDR1, and 4 expressed both drug resistance genes. In summary, MRP is frequently expressed in clinical samples and cell lines from SCLC patients, and the levels correlate with doxorubicin resistance in unselected SCLC cell lines. Expression of MDR1 can be detected in clinical samples of SCLC but is rarely found in cell lines from drug-resistant patients. These multidrug resistance proteins may contribute to the multifactorial problem of clinically acquired drug resistance in SCLC.