Background The benefit of neoadjuvant chemotherapy in the management of head and neck squamous cell carcinomas (HNSCC) still remains controversial. The aim of this meta-analysis is to evaluate the role of the neoadjuvant chemotherapy with the cisplatin and fluororacil (PF) regimen in enhancing the overall survival of and decreasing locoregional relapse and distant metastasis in HNSCC patients.Methods Medline and manual searches were performed to identify all published randomized controlled trials (RCTs) investigating the efficacy of the neoadjuvant chemotherapy with the PF regimen. Outcomes assessed by meta-analysis included Iocoregional relapse, distant metastasis, and overall survival. The odds ratio was the principle measurement of effect, which was calculated as the treatment group (chemotherapy plus Iocoregional treatment) versus the control group (Iocoregional treatment alone) and was presented as a point estimate with 95% confidence intervals (Cl).Results Eight RCTs were adopted for analysis. The meta-analysis showed that the odds ratio for the Iocoregional relapse was 0.92 (0.70-1.22, 95%Cl), which was not statistically significant. The odds ratios for distant metastasis and overall survival were 0.47 (0.33-0.68, 95% Cl) and 1.28 (1.01-1.62, 95% Cl) respectively, which were both statistically significant.Conclusions Neoadjuvant chemotherapy with the PF regimen in HNSCC patients has no effect on Iocoregional relapse. However, it shows a small but significant benefit in reducing distant metastasis and improving the overall survival.