Pneumonectomy is one of the important surgical methods for non-small cell lung cancer (NSCLC). This study evaluated the effects of laterality on the short- and long-term survival of NSCLC patients undergoing pneumonectomy. We reviewed the Surveillance, Epidemiology, and End Results database to retrieve the data of patients who underwent pneumonectomy for stage I-III NSCLC from 2004 to 2015. Propensity score matching (PSM) was used to reduce the selection bias. Logistic regression was used to analyze the correlation between laterality and mortality at 3, 6, and 9 months. The Kaplan-Meier curve was used to further assess the effect of laterality on overall survival (OS). A total of 4,763 patients met the enrollment criteria [right-sided, 1,988 (41.7%); left-sided, 2,775 (58.3%)]. After PSM, 1,911 patients for each side were included in the further analysis. The first 6 months following pneumonectomy was the main period of death, with 32.0% (428/1,336) and 19.9% (250/1,258) of right- and left-sided deaths occurring during this period. The logistic regression analysis showed that right-sided pneumonectomy was an independent risk factor for 3- (P<0.001) and 6-month (P<0.001) mortality. However, laterality had no significant effect on postoperative death at 7-9 months (P=0.82). In the total cohort, right-sided patients had worse OS (P<0.001), but the subgroup survival analysis of patients with a follow-up period >6 months revealed that laterality had no statistically significant effect on OS (P=0.75). Right-sided pneumonectomy was associated with a higher perioperative mortality risk that lasted about 6 months. After that period, laterality was not observed to have a significant prognostic effect on the OS of patients undergoing pneumonectomy.