The effect of response to first-line tyrosine kinase inhibitor (TKI) therapy on second-line survival in patients with metastatic renal cell carcinoma who receive second-line molecular-targeted therapy (mTT) after first-line failure remains unclear. Sixty patients who developed disease progression after first-line TKI, without prior cytokine therapy, were enrolled. According to the median first-line time to progression (1L-TTP), patients were divided into 2 groups (i.e., short vs. long). Second-line progression-free survival (2L-PFS) and second-line overall survival (2L-OS) were defined as the time from second-line mTT initiation. Survival was calculated with the Kaplan-Meier method and compared using the log-rank test between patients with short and long 1L-PFS. Predictors for survivals were identified using Cox proportional hazards regression models. The median 1L-TTP was 8.84 months. Thirty patients (50.0%) with short 1L-TTP (<8.84mo) had significantly shorter 2L-PFS and 2L-OS compared to patients with long 1L-TTP (2L-PFS: 4.96 vs. 10.2mo, P = 0.0002; 2L-OS: 9.6 vs. 28.0mo, P = 0.0036). Multivariable analyses for 2L-PFS and 2L-OS showed that 1L-TTP was an independent predictor both as a categorical classification (cutoff: 8.84mo) and as a continuous variable (both P<0.05). The median follow-up duration was 13.1 months (interquartile range: 6.56-24.7). Patients who achieve a long-term response after first-line TKI therapy could have a favorable prognosis with second-line mTT.