Objectives There is currently no consensus on the prognostic significance of the histological subtype of nasopharyngeal carcinoma (NPC). The aim of the current study was to evaluate the impact of histological subtype on survival in NPC patients based on the Surveillance, Epidemiology, and End Results (SEER) Program. Methods Patients with NPC were identified within the SEER database (2004-2015). The effects of histological subtype on cause-specific survival (CSS) in NPC patients were evaluated using univariate and multivariate Cox regression analyses. Subgroup analysis according to histological subtype in NPC patients was carried out by 1:1 propensity score matching (PSM). Results A total of 4085 NPC patients were selected from the SEER database, including 1929 with keratinizing squamous cell carcinoma (KSCC), 2203 with nonkeratinizing carcinoma (NKC), and 53 with basaloid squamous cell carcinoma (BSCC). The 3-year and 5-year CSS rates were 61.76% and 55.07% for KSCC patients, 79.57% and 72.09% for NKC patients, and 77.55% and 74.03% for BSCC patients, respectively. Multivariate analysis identified sex, age, marital status, race, T stage, N stage, M stage, radiotherapy, chemotherapy, and histological subtype as significant prognostic factors for CSS in NPC patients. KSCC was found to be associated with worse CSS than NKC on Kaplan-Meier analysis and subgroup analysis after 1:1 PSM. Conclusions Histological subtype determines the long-term survival outcomes of patients with NPC. Moreover, the NKC subtype has the best prognosis, while the KSCC subtype has the worst prognosis. Level of Evidence NA Laryngoscope, 130:E83-E88, 2020