The goal of this study was to assess the relationship between liver surface nodularity (LSN), chemotherapy-associated liver injury (CALI), and clinically relevant post-hepatectomy liver failure (CR-PHLF) (i.e., ≥ grade B) in patients undergoing hepatectomy for colorectal liver metastases (CLM). Preoperative CT scans of patients who underwent chemotherapy followed by hepatectomy for CLM between 2010 and 2017 were retrospectively analyzed. LSN was measured using semi-automated CT software CT images in patients who had available preoperative CT scans within 6 weeks before hepatectomy, and was computed based on the means of one to 10 measurements by two abdominal radiologists consensually. The association of LSN, CALI, and CR-PHLF was analyzed. Two hundred fifty-six patients were analyzed (149 men and 107 women; overall median age, 61 [range, 29-88 years]). A total of 26 patients (10.2%) developed CR-PHLF. The optimal LSN cut-off value for detecting CR-PHLF was 2.5, as determined by receiver operative characteristic analysis (p < 0.001). LSN ≥ 2.5 was associated with prolonged chemotherapy (> 6 cycles, p = 0.018), but not with CALIs. After propensity score matching, LSN remained significantly associated with CR-PHLF (p = 0.031). Furthermore, multivariate analysis identified LSN ≥ 2.50 and future liver remnant (FLR) < 30% as significant preoperative predictors of CR-PHLF in 102 patients undergoing major hepatectomy. LSN ≥ 2.50 was more frequent in patients undergoing major hepatectomy despite FLR ≥ 30% (p = 0.008). LSN quantified on CT is an independent surrogate of CR-PHLF in patients who undergo chemotherapy followed by hepatectomy for CLM and may provide a valuable additional tool in the preoperative assessment of these patients. • LSN was not associated with chemotherapy- associated liver injury but high LSN (defined ≥ 2.5) was associated with prolonged chemotherapy (> 6 cycles). • High LSN was an independent predictor of clinically relevant postoperative liver failure in patients undergoing hepatectomy for CRLM. • LSN ≥ 2.50 was more frequent in patients with PHLF after major hepatectomy despite a future liver remnant ≥ 30%.