Abstract: Objective: To investigate the correlation between clinically relevant nutritional indicators and prognosis in patients receiving pembrolizumab as second-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Methods: This retrospective analysis of 86 patients with R/M HNSCC treated with pembrolizumab admitted to Ninth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine from January 2019 to June 2021 was performed for survival prognosis analysis and risk factor assessment. Results: The median follow-up, median overall survival (OS), median progression-free survival (PFS) were 11.6 (3.0-25.9) months, 11.3 months and 8.3 months, respectively. Multifactorial analysis showed that underweight (OS: P=0.016; PFS: P=0.003), age≥60 years (OS: P=0.009; PFS: P=0.014), lower serum albumin (OS: P=0.013; PFS: P=0.010), performance status (PS) scores≥2 (OS: P<0.001; PFS: P=0.005), combined positive score (CPS)<1 (OS: P=0.009, PFS: P=0.006) and rⅣ stage (OS: P=0.011; PFS: P=0.003) were independent risk factors for increased risk of death. Overweight (OS:P=0.001; PFS: P=0.004) was an indicator of reduced mortality risk. Kaplan-Meier survival curve analysis showed that BMI and serum albumin levels were significantly associated with OS and PFS (P<0.001). Conclusions: The findings suggest that BMI, age, serum albumin, PS scores, CPS and clinical stage are significantly associated with the prognosis in R/M HNSCC patients treated with pembrolizumab and may serve as independent prognostic indicators of anti-PD-1 therapy in patients with R/M HNSCC.