Background: Second primary cancer (SPC) is not a rare event for patients with non-small cell lung cancer (NSCLC), especially for those who survive for a longer period of time. This study was aimed to explore the effects of SPC on the survival of NSLCL patients. Methods: A total of 241,805 patients with primary NSCLC were identified between 2004 and 2014 from the Surveillance, Epidemiology, and End Results (SEER) database. The incidence of SPC and its effect on the overall survival (OS) and lung cancer-specific survival (LCSS) was explored and analyzed using Cox regression model with SPC being treated as a time-dependent covariate. Results: The incidence of SPCs after the diagnosis of NSCLC was 6.4%, with the second primary lung cancer being the most common one (45.1%). About half of the SPCs (50.7%) occurred during the first year after the diagnosis of NSCLC. It seemed that patients who developed SPC late in the follow-up period tended to have poor prognosis. Multivariable analysis with Cox regression showed that the occurrence of SPC was a poor prognostic factor for patients with NSCLC [hazard ratio (HR), 1.298; 95% confidence interval (CI), 1.270-1.326; P=0.000], and it increased the risk of LCSS (versus no SPC, HR, 1.094; 95% CI, 1.066-1.123; P=0.000). Conclusions: The occurrence of SPC after the diagnosis of NSCLC was not a rare event, and it indicated a poorer prognosis compared with patients without it. During the follow-up, attention should be paid to the screening of SPC especially the second primary lung cancer, and a rational surveillance policy should be formed and implemented.