Objective Investigate the effect of guanylate binding protein GBP 5 expression on the treatment of head and neck squamous cell carcinoma HNSCC by observing the expression of GBP5 and immune - infiltrating cells in tumor and stromal cells. Method The correlation between GBP5 and immune-infiltrating score was analyzed by bioinformatics. 87 patients treated with HNSCC in the radiotherapy department of the first affiliated hospital of Hebei North University from August 2019 to January 2023 were analyzed retrospectively. Immunohistochemistry was used to observe the expression of GBP5 and programmed death-ligand 1 PDL1 flow cytometry was examined to immune-infiltrating cells. Result There was positive correlation between immune-infiltrating score and GBP5 which was screened from TCGA database. In tumor and stromal cells the positive expression rate of GBP5 was 58. 6% 51 / 87 and 42. 5% 37 / 87 respectively with significant difference in statistics χ 2 = 16. 805 P<0. 001 . There were statistically significant differences in pTNM stage PD-L1 between the positive and negative expressions of GBP5 all P<0. 05 . The levels of CD3 CD4 CD8 CD20 and CD68 in the positive expression of GBP5 were higher than those in the negative expression of GBP5 in stromal cells while the former was obviously lower than that in the latter in CD163 all P< 0. 05 . The expression of GBP5 was associated with PD-L1 expression CD8 CD68 cells respectively all P<0. 05 . Univariate and multivariate Cox regression analysis showed that the negative expression of GBP5 in stromal cells HR = 4. 66 was a poor factor for HNSCC prognosis P = 0. 005 however the negative expression of GBP5 in tumor cells and positive expression of GBP5 in stromal cells HR= 0. 04 CD68 HR= 0. 21 were protective factors for HNSCC all P<0. 05 . The sensitivity of CD68 level combined with GBP5 expression in stromal cells in evaluating the prognosis of HNSCC was 0. 82 the specificity was 0. 90 AUC was 0. 81 which was good diagnostic ability P< 0. 05 . The median tumor-specific survival rate of the positive expression of GBP5 was significantly better than that of the negative expression of GBP5 1620 d vs. 850 d HR = 0. 15 95% CI = 0. 05- 0. 42 P = 0. 001 . Stratified analysis showed that the median tumor-specific survival rate was optimal for the negative expression of GBP5 in tumor cells combined with positive expression of GBP5 in stromal cells 1620 d . In the analysis of high-level of CD68 subgroup the median tumor-specific survival rate was better in positive expression of GBP5 than that in negative expression of GBP5 in stromal cells 1620 d vs. 850 d . In the analysis of the subgroup with high and low expressions of PD-L1 the median tumor-specific survival rate in the positive expression of GBP5 was significantly longer compared to the negative expression of GBP5. Conclusion The expression of GBP5 in stromal cells might be closely related to CD68 levels which may serve as a supplementary marker for negative expression of PD-L1 compared to that in tumor cells.