Ubiquitin-specific proteases (USPs) are closely related to protein fate and cellular processes through various molecular signalling pathways, including DNA damage repair, p53, and transforming growth factor-β (TGF-β) pathways. In recent years, increasing evidence has revealed the pivotal role of ubiquitination in tumorigenesis of KIRC. However, USPs' molecular mechanism and clinical relevance in kidney cancer still need further exploration. Our study first determined prognosis-related ubiquitin-specific proteases (PRUSPs) in KIRC. We found these genes co-expressed with each other and might regulate different substrates. Based on the USPs' expression, the PRUSPs risk signature was constructed to predict the survival probability of KIRC patients. The patients in high-PRUSPs-risk group showed a low survival rate. ROC and calibration curve indicated a discriminate capacity of the signature, and uni-/multi-variate Cox regression analysis revealed that the PRUSPs score is an independent prognostic factor. In different KIRC clinical subgroups and external validation cohorts (including E-MTAB-1980 and TCGA-KIRP cohorts), the PRUSPs risk signature showed strong robustness and practicability. Further analysis found that high-risk group showed activation of immune-related pathways and high PD-1/CTLA4 expression, revealing that high-risk patients might be sensitive to immunotherapy. In summary, we constructed the USPs risk signature to predict kidney cancer prognosis, which provided the theoretical foundation for further clinical or pre-clinical experiments.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12882-023-03215-0.