Simple SummaryClear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer. Although it ranks as the seventh most diagnosed type of cancer, ccRCC is increasingly prevalent in the Western world. While most cases of ccRCC are diagnosed in the early stages, the cancer can often progress, spread to distant organs, and recur after treatment. Assessing the survival of ccRCC patients, and thus the aggressiveness of the cancer, can help clinicians make more informed decisions on patient management. We employed a systematic approach to find new biomarkers that can improve patient survival prediction. Our research revealed that increased expression of the COL7A1 gene is correlated with an aggressive form of the cancer and improve patient survival assessment, complementing the clinical characteristics that are already in use for survival prediction. Furthermore, our findings indicate that COL7A1 is a robust biomarker, that can be applied to patients of different origins and who undergo different treatment procedures. Interestingly, preliminary experiments led to the hypothesis that COL7A1 may play a role in cancer progression.AbstractClear-cell renal cell carcinoma (ccRCC) accounts for 75% of kidney cancers. Due to the high recurrence rate and treatment options that come with high costs and potential side effects, a correct prognosis of patient survival is essential for the successful and effective treatment of patients. Novel biomarkers could play an important role in the assessment of the overall survival of patients. COL7A1 encodes for collagen type VII, a constituent of the basal membrane. COL7A1 is associated with survival in many cancers; however, the prognostic value of COL7A1 expression as a standalone biomarker in ccRCC has not been investigated. With five publicly available independent cohorts, we used Kaplan–Meier curves and the Cox proportional hazards model to investigate the prognostic value of COL7A1, as well as gene set enrichment analysis to investigate genes co-expressed with COL7A1. COL7A1 expression stratifies patients in terms of aggressiveness, where the 5-year survival probability of each of the four groups was 72.4%, 59.1%, 34.15%, and 8.6% in order of increasing expression. Additionally, COL7A1 expression was successfully used to further divide patients of each stage and histological grade into groups of high and low risk. Similar results were obtained in independent cohorts.In vitroknockdown of COL7A1 expression significantly affected ccRCC cells’ ability to migrate, leading to the hypothesis that COL7A1 may have a role in cancer aggressiveness. To conclude, we identified COL7A1 as a new prognosis marker that can stratify ccRCC patients.