Purpose: The aim of this study was to determine the prognostic value of systemic inflammatory indices as factors for postoperative complications and survival in patients with advanced stages of p16-negative head and neck squamous cell carcinoma undergoing free-flap reconstruction. Methods: This was a retrospective cohort study. The primary predictor variables were inflammatory markers such as neutrophil, lymphocyte, monocyte, and platelet count, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, lymphocyte-monocyte ratio, derived NLR, systemic immuneinflammatory index, and systemic inflammatory marker index (SIM). Multivariate regression analyses were used to measure the associations between systemic inflammatory indices and overall and diseasefree survival as a primary outcome and occurrence of postoperative complications as a secondary outcome measure. Results: The sample was composed of 69 male (76.67%) and 21 female (23.33%) patients, with an average age of 61.15 9.79 years. The median follow-up time was 24 months, and 73 of 91 (66.43%) patients were alive during the median follow-up. Overall disease survival correlated with systemic immune-inflammation (P = .022, cutoff >1,005.3, sensitivity 67.1%, and specificity 70.6%) and SIM (P = .0001, cutoff >4.05, sensitivity 90.4%, and specificity 41.2%), preoperative platelets (P = .036, cutoff <194, sensitivity 28.8%, and specificity 94.1%), and postoperative lymphocytes (P = .012, cutoff <0.6, sensitivity 38%, and specificity 76.5%), whereas increased SIM (P = .042, cutoff >4.05, sensitivity 91.3%, and specificity 38.1%), NLR (P = .031, cutoff >13.2, sensitivity 56.9%, and specificity 60%), and preoperative platelets (P = .006, cutoff <244, sensitivity 52.3%, and specificity 76%) were associated with adverse disease-free survival. The cumulative postoperative complication rate was 34.5%, of which 13.3% accounted for major complications, whereas derived NLR (P = .013, degrees of freedom 1, c2 test 6.161, cutoff >2.3) and postoperative lymphocytes (P = .009, DF 1, c2 test 6.756, cutoff <1) correlated with occurrence of complications. Conclusions: Inflammatory indices as measures of inflammation-related systemic dysfunction may be associated with adverse survival in patients with head and neck squamous cell carcinoma and occurrence of postoperative complications and with specific cutoff values.