Human lung cancer cells, including small cell lung carcinoma (SCLC), frequently lose expression of retinoic acid receptor โค (RAR-โค) and are resistant to the growth inhibitory activity of all-trans retinoic acid (RA). To elucidate the role of RAR-โค in the growth regulation of SCLC by retinoids, we restored RAR-โค expression in RAR-โค-negative H209 SCLC cells by retroviral transduction (H209-RAR-โค). We found that H209-RAR-โค, but not parental H209 cells, underwent growth inhibition upon RA treatment. RA-treated H209-RAR-โค cells arrested in G 1 and displayed reduced L-myc expression and cyclin-dependent kinase 2 (cdk2) activity compared with untreated cells. RA treatment of H209-RAR-โค cells was also accompanied by increased expression of the cdk inhibitor p27 Kip1 , whereas no differences in the expression of L-myc or p27 Kip1 were detected upon RA treatment of parental H209 cells. The RA-induced growth arrest of H82 SCLC cells, which express endogenous RAR-โค, was also associated with reduced c-myc and increased p27 Kip1 expression. We found that ectopic expression of p27 Kip1 induced growth inhibition in both H209 and H82 cells, and that sustained myc expression in H209-RAR-โค cells promoted the induction of apoptosis upon RA addition. Our observations indicate that RAR-โค gene transfer can restore RA sensitivity in SCLC cells and suggest that myc and p27 Kip1 may represent critical mediators of the RA-induced cell cycle arrest in SCLC cells expressing RAR-โค.