Neoadjuvant therapy (NAT) is increasingly used to treat patients with initially unresectable intrahepatic cholangiocarcinoma (iCCA). A histopathologic grading system for residual tumors that can predict patient survival is lacking in the literature. This retrospective study enrolled 151 iCCA patients who received NAT. The percentage of residual viable tumor (%RVT) extent was calculated by RVT surface area/total tumor bed area ×100 and scored in 5% increments. Kaplan-Meier and Cox regression analyses were used to investigate its correlations with recurrence-free survival (RFS) and overall survival (OS). Tumor regression grading by the College of American Pathologists (CAP) and MD Anderson (MDA) methodologies were also validated. A 10% RVT-based tumor regression score (TRS) showed a significant correlation with both OS and RFS. TRS and major pathologic response (mPR) were therefore defined as follows: TRS 1/mPR, tumor with 0 to 10% RVT; TRS 2, more than 10% RVT. Patients graded as TRS 1/mPR had superior OS ( P =0.006) and RFS ( P <0.001) compared with those with TRS 2 in univariate analysis. In a multivariate analysis including ypTNM stages, lymphovascular invasion, and perineural invasion, TRS 1/mPR was also found to be an independent prognostic factor for both OS (hazard ratio [HR]: 0.226; 95% CI: 0.053-0.966, P =0.045) and RFS (HR: 0.474; 95% CI: 0.231-0.974, P =0.042). As for the CAP and MDA grading methodologies, they were found to correlate with RFS (CAP: P =0.002; MDA: P =0.001), but not with OS (CAP: P =0.181; MDA: P =0.09). Our study revealed that a TRS of ≤10% RVT significantly correlates with longer OS and RFS and can be suggested as an mPR in iCCA. This indicator is easily applicable, prognostically relevant, and could be further validated in future prospective clinical trials.