<p>Recent studies have revealed the prognostic value of genetic alterations in intrahepatic cholangiocarcinoma (ICC). However, the influence of individual mutations on postoperative recurrence has not been comprehensively evaluated, especially for lymph node-negative cases. A total of 589 localized ICCs with clinically or pathologically negative lymph node (cN0M0 or pN0M0) from 3 independent cohorts were included. The impact of clinicopathological and mutational parameters on recurrence-free survival (RFS) and post-recurrence survival (PRS) was analyzed using the Cox proportional hazards model. The effect of prognostic mutations on RFS and PRS was estimated by Kaplan–Meier analysis. Extremes of survivorship analysis was used to reveal distinct genomic profiles between cases with very early recurrence (VER) and long-term no recurrence (LNR). Among the recurrent mutations, only <i>TP53</i> and <i>KRAS</i> showed significant association with RFS in both of the two screening cohorts. In the validation cohort, <i>TP53</i> and <i>KRAS</i> mutations were both independent predictors for shorter RFS. Compared with wild-type patients, <i>TP53</i> and <i>KRAS</i> mutations were more frequently observed in VER group than in LNR group, and were more enriched in patients with intrahepatic and extra-hepatic recurrence (IER). Furthermore, <i>TP53</i> mutation was significantly associated with worse survival and lower probability of repeated hepatectomy in patients suffered from recurrence. <i>TP53</i> and <i>KRAS</i> mutations were important genetic predictors that correlated with earlier and more aggressive recurrence in node-negative ICC patients after surgery. Effective peri-operative therapies for these high-risk tumor biology are needed to improve the clinical outcome for related patients.</p>