The objective of this study was to determine periplakin expression in normal urothelium and bladder cancer tissues and the relationship to clinicopathological findings. Immunohistochemical staining for periplakin was carried out in 92 archival radical cystectomy specimens, with immunoreactivity being stratified on a 0-6 scale. Immunohistochemical staining for periplakin was shown to be significantly lower in bladder cancer tissues compared to non-cancerous tissues including inflammation,hyperplasia and normal urothelium. Loss of periplakin expression was associated with pathological stage (P=0.04). In multivariate Cox regression analysis, loss of periplakin expression and positive lymph node status were independent prognostic factors for cancer-specific survival (P=0.03 and 0.015; odds ratio=2.29 and 2.66; 95% confidence interval=1.085-4.814 and 1.214-5.845, respectively). This new molecular marker may aid in identifying and selecting bladder cancer patients undergoing radical cystectomy who may potentially benefit from neoadjuvant or adjuvant therapy.