In this study, the researchers aimed to learn more about how centromeric protein A (CENPA) gene expression is associated with the prognosis of papillary renal cell carcinoma (PRCC). Information on PRCC cases in TCGA was gathered. Next, the Wilcoxon rank-sum test was used to compare the CENPA levels of the PRCC and non-carcinoma samples, and logistic regression and the Wilcoxon rank-sum test were used to assess the associations between clinicopathological features and CENPA expression. Area under the receiver operating characteristic curve (ROC) plot was used to evaluate CENPA’s prognostic usefulness (AUC). Moreover, Kaplan-Meier (KM) and Cox regression analyses were used to examine the associations between clinicopathological features and PRCC survival. The researchers divided the total number of patients into 2 groups, the trial cohort and the validation cohort, with a 7:3 split, and used multivariate Cox regression results to create a nomogram in the trial cohort to predict how CENPA affected patient survival. The researchers then used the calibration curve to ensure that the nomogram was accurate in both groups. Furthermore, they used immunohistochemistry to compare CENPA expression between cancer and non-carcinoma tissues with similar histological characteristics (IHC). Finally, they used functional enrichment to determine important pathways associated with DEGs in PRCC cases displaying either up- or down-regulation of CENPA. Compared to normal tissues, PRCC tissues showed significantly higher CENPA expression (P<0.001). The pathological TNM stage and the clinical stage were correlated with the up-regulation of CENPA (P<0.05). Meanwhile, ROC curves showed that CENPA had exceptional diagnostic power for PRCC, and its expression can greatly enhance the predicted accuracy of pathological TNM stage and clinical stage for PRCC. (Risk ratio=3.07, 95% confidence interval (CI)=1.58-5.97, P=0.001; Kaplan-Meier (KM) curves showed a significant difference in survival rates between PRCC cases with up- and down-regulation of CENPA. Furthermore, both univariate and multivariate analyses found that CENPA was independently associated with overall survival (OS, P<0.05), and the nomogram exhibited greater prediction power in both cohorts. Results from an immunohistochemical study demonstrated a higher CENPA positivity rate in PRCC cases compared to controls. According to the results of the functional annotations, CENPA is highly represented in the pathways involving interactions with neuroactive ligand receptors, cytokine receptors, extracellular matrix regulators, extracellular matrix glycoproteins, and the nuclear matrisome. An uptick in the expression of CENPA within PRCC samples is an indicator of poor prognosis for PRCC. CENPA shows promise as a therapeutic target and molecular prognostic marker in individuals with PRCC.