Background: Immunotherapy-tyrosine kinase inhibitor (IO-TKI) and tyrosine kinase inhibitor (TKI) are the main treatment strategies that have significantly improved outcomes of metastatic renal cell carcinoma (mRCC) patients. However, there are no effective biomarkers available to predict the efficacy of these regimens. We aim to explore the predictive value of serum immunoglobulin G (IgG) in systemic treatment. Methods: The study consisted of 292 mRCC patients who received TKI or IO-TKI therapy. Serum IgG in the pre-treatment baseline, 1 month, and 3 months after systemic treatment were measured using the immunoturbidimetric method. The Wilcox test was used to compare baseline serum IgG levels and paired t-test was utilized to compare serum IgG levels between baseline and 3 months after treatment. Kaplan-Meier curve were used to evaluate the PFS and Cox proportional hazard regression analysis was conducted to identify independent determinant factors for PFS. Results: The baseline level of IgG was not associated with objective response rate (ORR) in the overall patient cohort. However, there was a significant decrease in IgG in patients achieving CR/PR and an increase in patients with SD/PD after 3 months of treatment (p<0.05). In the TKI cohort, the estimated 9-month PFS was significantly higher in the IgG-decrease group versus the IgG-increase group (HR 2.5, 95%CI 1.8-3.4, p<0.001). The results were similar in the IO-TKI cohort. The predictive value of alteration of IgG after 1-month treatment was demonstrated in terms of the estimated 9-month PFS (HR 1.5, 95%CI 1.0-2.3, p=0·048). The ROC curve showed outstanding performance of alteration of serum IgG in predicting PFS. Conclusions: Alteration of serum IgG after systemic treatment is a reliable biomarker to predict the efficacy in mRCC patients. The change of IgG after 1-month treatment could serve as indicator of treatment efficacy and improve individualized drug selection. Further validation is warranted.