SETD2 (SET domain containing protein 2) is a histone H3K36 trimethyltransferase protein that associates with hyperphosphorylated RNA polymerase II and involves in transcriptional elongation. However, whether and how SETD2 is implicated in the specific regulation of gene transcription remains unknown. Here we show that SETD2 could interact with p53 and selectively regulate the transcription factor activity of p53. The interaction was dependent of C-terminal region of SETD2, which contains the SET and WW domains, and the N-terminal transactivation domain (residues 1-45) of p53. Overexpression of SETD2 upregulated the expression levels of a subset of p53 targets including puma, noxa, p53AIP1, fas, p21, tsp1, huntingtin, but downregulated that of hdm2. In contrast, it had no significant effect on those of 14-3-3sigma, gadd45 and pig3. Consistently, knockdown of endogenous SETD2 expression by RNA interference resulted in converse effects as expected. In p53-deficient H1299 cells, SETD2 lost the ability to regulate these gene expression except hdm2, indicating the dependence of p53. Furthermore, we demonstrated that SETD2 downregulated hdm2 expression by targeting its P2 promoter and then enhanced p53 protein stability. Collectively, these findings suggest that the histone methyltransferase SETD2 could selectively regulate the transcription of subset genes via cooperation with the transcription factor p53.