The anti-diabetic thiozolidinedione compound pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, has been found to have growth inhibitory effects in some cancer cells. The mechanism underlying this growth suppression is not well understood. In this study, we evaluated the effect of pioglitazone on p53 and p21 expression in various cancer cell lines with different p53 status. The cells with wild type p53 did not show any change in p53 levels in response to pioglitazone. Also, none of the cell lines exhibited p53-dependent or independent transcriptional induction of p21(WAF1/CIP1) by pioglitazone. However, PC3, an androgen-insensitive prostate cancer cell line with deletion of p53 showed an appreciable post-transcriptional induction of p21 expression after treatment with pioglitazone. These results imply that pioglitazone generally does not modulate p21 transcription in human cancer cell lines.