Background: The efficacy of systemic therapy regimens, such as immune checkpoint inhibitors and tyrosine kinase inhibitors (IO-TKI) and targeted therapy, for metastatic clear cell renal cell carcinoma (ccRCC) remains unpredictable due to the lack of effective biomarkers. This study investigates the predictive value of neutrophil extracellular traps (NETs) in determining the efficacy of metastatic ccRCC. Methods: In this retrospective study, patients with metastatic ccRCC who received targeted drugs and IO-TKI were included. Immunofluorescence staining was utilized to quantify the levels of tissue NETs through cell counts of H3Cit(+) and MPO(+) cells. The correlation between NETs and clinicopathological features was analyzed, and the predictive value of NETs for drug efficacy and prognosis was assessed using Cox proportional hazard analysis. Results: A total of 183 patients with metastatic ccRCC were enrolled, including 150 patients who received TKIs and 33 patients who received IO-TKI. H3Cit and MPO were predominantly expressed in the nucleus and cytoplasm, respectively. The levels of NETs in tumor tissue were significantly higher than in para-tumor tissue (p<0.001). Increased levels of NETs in tumor tissue were associated with tumor N stage (p=0.02) and neutrophil-to-lymphocyte ratio (NLR) (p=0.02). In terms of predicting drug efficacy, a correlation between NETs levels and progression-free survival (PFS) was observed in the TKI with metachronous metastasis group (HR 1.73 [95% CI 1.02-2.91], log-rank p=0.037), while no correlation was observed in the targeted agent with synchronous metastasis group and IO-TKI group. Regarding overall survival (OS), activated NETs levels were associated with poor OS (HR 1.87 [95% CI 1.24-2.81], log-rank p=0.003). Cox analysis revealed that IMDC score (HR 1.462 [95% CI 1.030-2.075], p=0.033) and tumor tissue NETs level (HR 1.733 [95% CI 1.165-2.579], p=0.007) were independent prognostic risk factors for OS in patients with metastatic ccRCC. Conclusions: The active NETs level in tumor tissue can serve as a predictor of drug efficacy in patients with metastatic ccRCC who received targeted agents with metachronous metastasis. However, no significant correlation was observed in the IO-TKI group, and further investigation is required. Elevated levels of NETs in tumor tissue were also associated with poor prognosis in OS prediction.