To investigate the clinical value of the expression levels of tumor protein D52 (TPD52) and miR-133a on the prognosis assessment of pancreatic cancer surgery. This was a retrospective study. Ninety-seven patients who underwent radical surgery for pancreatic cancer in Cangzhou Central Hospital from January 2018 to January 2022 were selected and divided into four groups: TPD52 high expression group, TPD52 low expression group, miR-133a high expression group and miR-133a low expression group. The relationship between the expression levels of TPD52 and miR-133a and the clinicopathological features of patients with pancreatic cancer was analyzed. The COX regression model was used to analyze the risk factors affecting the prognosis of patients with pancreatic cancer. The high expression rate of TPD52 and the low expression rate of miR-133a in pancreatic cancer tissues were higher than those in normal paracancerous tissues(P<0.05). Based on the comparison of prognosis and survival, the median survival time of patients with high expression of TPD52 and low expression of miR-133a was lower than that of patients with low expression of TPD52 and high expression of miR-133a, with a statistically significant difference(P<0.05). Moreover, multivariate Cox regression analysis showed that low differentiation of pancreatic cancer, III-IV stage of TNM, high expression of TPD52, as well as low expression of miR-133a were independent risk factors for postoperative survival of patients with pancreatic cancer(P<0.05). TPD52 is expressed at a high level whereas miR-133a at a low level in pancreatic cancer tissues, both of which together with low differentiation of pancreatic cancer and III-IV stage of TNM constitute independent risk factors affecting the surgical prognosis of patients with pancreatic cancer.