To investigate the effect of chemotherapy versus no chemotherapy on the risk of second primary head and neck malignancies (SPHNMs) in patients with locally advanced oral squamous cell carcinoma (OSCC) and to assess the survival outcomes of patients with SPHNM.A total of 937 OSCC patients were divided into chemotherapy and nonchemotherapy groups by propensity score matching (PSM). In the presence of the competing event of non-SPHNM death, the fine and gray modified Cox proportional hazard model was fitted to detect the impact of various factors, including the history of chemotherapy, on SPHNM risk. The Kaplan-Meier method was used to assess the survival outcomes of patients.After PSM, the 10-year cumulative probability of SPHNM was 10.7% for patients who received chemotherapy and 22.1% for patients who did not. The fine and gray regression model showed that prior chemotherapy was associated with a 51% reduced risk of SPHNM (adjusted subdistribution hazard ratio (sHR): 0.49, 95% confidence interval (CI): 0.29-0.84, P = 0.1). The disease-free survival (DFS) rates did not differ significantly between the SPHNM and non-SPHNM groups. And there were no significant differences in DFS rates between the patients with and those without prior chemotherapy in the SPHNM group.Chemotherapy for locally advanced primary OSCC is associated with a decreased incidence of subsequent SPHNM. However, chemotherapy for the primary cancer does not improve DFS in patients with SPHNM.Chemotherapy plays a positive role in preventing SPHNMs for patients with oral squamous cell carcinoma.Before January 2015, the data were retrieved retrospectively, while after January 2015, the data were collected prospectively in a POROMS database (ClinicalTrials.gov ID: NCT02395367).© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.