The evidence for adjuvant therapy of oral cavity squamous cell carcinoma (OCSCC) in NCCN guidelines derives from patients with head and neck cancer. Here, we examined whether adjuvant therapy should be guided by a detailed analysis of pathological risk factors in pure OCSCC patients.Between 2004 and 2016, we retrospectively reviewed 1200 consecutive OCSCC patients who underwent radical surgery and neck dissection in the XXX Hospital (XXXH). Patients were divided into three prognostic groups. High-risk patients were those with extra-nodal extension and/or positive margins (ENE/margins+, n=267). Intermediate-risk patients were further divided into three subgroups: 1) patients in whom adjuvant therapy was indicated according to the XXXX but not the NCCN guidelines (NCCN[-]/XXXX[+], n=14); 2) patients in whom adjuvant therapy was indicated by the NCCN but not the XXXX guidelines (NCCN[+]/XXXX[-], n=160); and 3) patients in whom adjuvant therapy was indicated according to both guidelines (NCCN[+]/XXXX [+], n=411). Low-risk patients were those for whom adjuvant therapy was not suggested in light of both guidelines (NCCN[-]/XXXX[-], n=348).According to NCCN guidelines, postoperative adjuvant therapy was indicated in 69.8% of the participants. However, only 57.7% of the patients were in need of adjuvant therapy by XXXX guidelines. The following 5-year outcomes were observed in the NCCN(-)/XXXX(-), NCCN(-)/XXXX(+), NCCN(+)/XXXX(-), NCCN(+)/XXXX(+), and ENE/margins+ subgroups: loco-regional control, 88%/70%/83%/79%/68%, P<0.001 (NCCN[+]/XXXX[-] vs. NCCN[+]/XXXX[+], P=0.576), distant metastases, 2%/7%/2%/9%/36%, P<0.001 (NCCN[+]/XXXX[-] vs. NCCN[+]/XXXX[+], P=0.003), disease-specific survival, 97%/86%/94%/84%/56%, P<0.001 (NCCN[+]/XXXX[-] vs. NCCN[+]/XXXX[+], P<0.001), and overall survival, 92%/86%/87%/68%/42%, P<0.001 (NCCN[+]/XXXX[-] vs. NCCN[+]/XXXX[+], P<0.001), respectively.Patients in the NCCN(+)/XXXX(-) subgroup, 28% (160/571[160+411]) of NCCN intermediate-risk patients, had more favorable 5-year disease-specific/overall survivals (94%/87%) than NCCN(+)/XXXX(+) subgroup. The former are unlikely to derive clinical benefits from NCCN guidelines. The 70% adjuvant therapy rate required by NCCN guidelines after radical surgery might be too high, ultimately leaving room for improvement.