Among 468 patients with oropharyngeal cancer treated at initial diagnosed, 222 cases were P16-negative. With a median follow-up time of 64.3 months, 66 cases developed second primary cancer, with an incidence of 29.3%, among which 63.6%(42/66) were synchronous and 36.4%(24/66) were heterochronous, esophagus was the most commonly involved site. The 5-year OS of p16-negative oropharyngeal carcinoma with synchronous second primary cancer, without second primary cancer and with heterogeneous second primary cancer were 26.3% and 57.3% and 73.2%(P=0.001); The second primary cancer accounted for 11.2%(12/107) of the deaths in the whole group, among them, the heterochronous second primary accounted for 75.0%(9/12). There were 246 patients with p16 positive, with a median follow-up time of 52.4 months, 20 patients developed second primary cancer(8.1%). Among them, 65.0%(13/20) were synchronous and 35.0%(7/20) were heterochronous. Esophagus was the most commonly involved site. The 4-year OS of p16-positive with synchronous, heterochronous and non-second primary cancer group were 51.9%, 80.7% and 83.3%. Secondary primary cancer accounted for 3.8%(2/52) of all deaths in p16 positvie group.