||The prenyl diphosphate synthase subunit 2 (PDSS2) gene has recently been proposed as a novel tumor suppressor in several types of solid tumors. However, the mechanism of its tumor-suppressing activity is not known. Our previous study found a decreased expression of PDSS2 in clinical samples of non-small-cell lung cancer, and an inverse correlation between PDSS2 levels and stages of tumor differentiation and lymph node metastasis. In this study, we further investigated the tumor-suppressing activity of PDSS2 in lung cancer cells using cellular and molecular tools. The PDSS2 gene has low levels of expression in human lung cancer cell lines. We transfected and overexpressed PDSS2 in the NCI-H1299 lung cancer cell line. The forced overexpression caused massive cell death (∼70%) through apoptotic pathways and significantly inhibited colony formation. At the same time, repression of PDSS2 expression by siRNA enhanced the growth of a noncancerous lung epithelial cell line MRC-5. There was an inverse correlation (Pearson's test, r=-0.9373) between PDSS2 expression and gelsolin expression, which is known to inhibit apoptosis and enhance cell invasion and metastasis. The ability of PDSS2 to repress gelsolin might contribute to its tumor-suppressing activity. However, PDSS2 did not influence the sensitivity of the lung cancer cells to chemotherapeutic drugs. Taken together, PDSS2 has tumor-suppressing activity in human lung cancer cells by enhancing apoptosis and inhibiting tumorigenic capacity.