Caveolin-1 (CAV-1) has been reported to play an important role in the development of a variety of human cancers. CAV-1 expression is revealed to be reduced or absent in the malignant tumor cells of small cell lung cancers (SCLC). This study was performed to investigate the influences of the stable expression of CAV-1 on the metastasis and proliferation of SCLC in vitro. The wild-type CAV-1 gene was successfully transfected into the NCI-H446 cells and was stably expressed in the NCI-H446 cells. The effects of CAV-1 on the morphology, proliferation, and metastasis potential for NCI-H446 cell were evaluated by crystal violet staining, MTT analysis, transwell assay, and scratch wound assay, respectively. Western blot and gelatin zymography were used to examine the expression changes of the metastasis-related MMP-3 and E-cadherin. Stable expression of CVA-1 was observed in the H446-CAV-1 cells, which enlarged the cell shape with filopodia. The proliferation of H446-CAV-1 was inhibited, while its migration and invasion abilities were promoted in vitro. The re-expression of CAV-1 reduced the expression of E-cadherin, while it increased the protein expression and enzyme activity of MMP-3. Taken together, the cellular proliferation of the NCI-H446 could be inhibited by the re-expression of CAV-1. CAV-1 might increase the cell metastasis potential through the interaction with E-cadherin and MMP-3 genes. These in vitro findings confirm the involvement of CAV-1 in the proliferation and metastasis of SCLC. Anat Rec, 2009. © 2009 Wiley-Liss, Inc.