TNF receptor-associated factor 2 (TRAF2) is documented to regulate tumor development and progression. Currently, the effect of TRAF2 on growth of androgen-refractory prostate cancer in response to TRAIL and the molecular mechanisms are not well understood. Here, we aim to investigate the effect of TRAF2 on in vitro growth of human androgen-insensitive prostate cancer DU-145 cells in the presence of TRAIL. Bioinformatics analysis of the Cancer Genome Atlas (TCGA) data was performed to examine TRAF2 expression and the prognostic value in prostate cancer. Microarray data of GSE21032 dataset were downloaded from Gene Expression Omnibus (GEO) to explore TRAF2 expression in metastatic prostate cancer. Bioinformatics analysis was further conducted to investigate the association of TRAF2 expression with recurrence-free survival in prostate cancer patients. Colony formation, cell viability, and Annexin V/PI apoptosis assays were performed to investigate the effect of TRAF2 on in vitro growth and apoptosis in TRAIL-treated DU-145 cells. The expression levels of mRNA and protein were detected by quantitative RT-PCR and immunoblotting assays. Bioinformatics analysis indicated that TRAF2 expression is significantly upregulated in prostate cancer patients with high Gleason scores (GS>7) compared with those with low Gleason scores (GS≤7). Upregulation of TRAF2 expression is significantly associated with recurrence-free survival in patients. In addition, TRAF2 knockdown can enhance apoptosis and downregulate SIRT1 expression in TRAIL-treated DU-145 cells. In vitro experiments further showed that SIRT1 knockdown can inhibit growth, and promote apoptosis in TRAIL-treated DU-145 cells. Overall, TRAF2 can influence in vitro growth of TRAIL-treated DU-145 cells at least partially via regulating SIRT1 expression, and may be a potentially valuable biomarker predicting recurrence-free survival in prostate cancer patients.