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 immune-inflammatory index, and systemic inflammatory marker index (SIM). Multivariate regression analyses were used to measure the associations between systemic inflammatory indices and overall and disease-free 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, χ2 test 6.161, cutoff >2.3) and postoperative lymphocytes (P = .009, DF 1, χ2 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.