Background <p>Colorectal cancer liver metastasis remains a significant challenge, with systemic inflammation and liver fibrosis emerging as key prognostic factors. This study evaluates the individual and combined prognostic significance of the Systemic Inflammation Index and Fibrosis-4 index in CRLM patients undergoing curative liver resection after neoadjuvant chemotherapy.</p> Methods <p>A retrospective cohort of 255 CRLM patients was stratified into high/low SII and FIB-4 groups based on median values. SII and FIB-4 were calculated using preoperative laboratory data. Primary outcomes included overall survival (OS) and disease-free survival (DFS), with secondary outcomes assessing postoperative complications and recurrence. Kaplan-Meier analysis and Cox regression were used for survival analysis.</p> Results <p>Higher SII levels were associated with worse DFS (HR = 0.67, <i>p</i> = 0.028). Similarly, higher FIB-4 levels correlated with increased recurrence rates (<i>p</i> = 0.03) and poorer DFS (HR = 0.69, <i>p</i> = 0.047). For Overall Survival (OS), no significant difference was observed between the High SII and Low SII groups, nor between the High FIB-4 and Low FIB-4 groups. The Low FIB-4 &amp; Low SII group showed significantly better DFS (HR = 0.47, <i>p</i> = 0.048). In terms of postoperative outcomes, the FIB-4 Low group had more transfusions and incision infections. Additionally, the SII High group had higher recurrence rates and more R1 resections (<i>p</i> = 0.045).</p> Conclusion <p>SII and FIB-4 are valuable biomarkers for predicting DFS and recurrence in CRLM patients. Their combined use enhances risk stratification, offering a comprehensive approach to guide personalized treatment strategies. Future studies should explore targeted therapies to modulate inflammation and fibrosis, improving outcomes for high-risk patients.</p>