Background The enhanced recovery after surgery (ERAS) pathway is increasingly used in head and neck cancer surgery with free tissue transfer reconstruction (HNS-FTR), but the role of preoperative corticosteroids remains unclear. This study assessed their impact on postoperative recovery. Methods This phase III, placebo-controlled, randomized, double-blind trial included 180 patients undergoing HNS-FTR. Patients were assigned (1:1) to receive 8 mg dexamethasone or placebo preoperatively. All received standardized ERAS care. The primary endpoint was postoperative recovery, assessed by the area under the curve (AUC) of Quality of Recovery Score (QOR-40J) on postoperative days 2 and 4, as patient-reported outcomes were not feasible on day 1. Secondary endpoints included AUC of visual analog scale (VAS) scores for pain and nausea on days 1–3. Systemic inflammatory response (SIR) was evaluated. Results Of 180 patients randomized, 178 underwent surgery and were analyzed (87 dexamethasone, 91 placebo); two did not undergo surgery. ERAS completion rates were 97.7% and 97.8%, respectively. AUC for QOR-40J scores on days 2 and 4 showed no significant difference (295.7 vs 299.8; p = 0.665). No differences were observed in pain (p = 0.828) or nausea (p = 0.649). Interleukin-6 levels were significantly lower with dexamethasone immediately after surgery and on day 1 (p < 0.001). However, dexamethasone did not improve recovery or reduce hospitalization. Conclusions Preoperative dexamethasone suppressed inflammation but did not improve recovery, pain, or nausea after HNS-FTR, suggesting inflammation control alone may be insufficient. Encore abstract: This abstract is an encore of the presentation at ASCO 2025 (Chicago).