ImportanceTyrosine kinase inhibitors (TKIs) have been recognized as the standard treatment for patients with non–small cell lung cancers (NSCLCs) and epidermal growth factor receptor (EGFR) sequence variation. Although TKIs have been reported to cause cardiotoxicity, they are widely administered owing to the high prevalence ofEGFRsequence variation in Taiwan.ObjectiveTo compare the outcomes of death and major adverse cardiac and cerebrovascular events among patients with NSCLC who use and do not use TKIs in a national cohort.Design, Setting, and ParticipantsUsing data from the Taiwanese National Health Insurance Research Database and National Cancer Registry, patients treated for NSCLC from 2011 to 2018 were identified, and their outcomes were analyzed, including death and major adverse cardiac and cerebrovascular events (MACCEs; such as heart failure, acute myocardial infarction, and ischemic stroke) after adjusting for age, sex, cancer stage, comorbidities, anticancer therapies, and cardiovascular drugs. The median follow-up duration was 1.45 years. The analyses were performed from September 2022 to March 2023.ExposuresTKIs.Main Outcomes and MeasuresCox proportional hazards models were used to estimate death and MACCEs in patients treated with and without TKIs. Given that death may reduce the incidence of cardiovascular events, the competing risk method was used to calculate the MACCE risk after adjustment for all potential confounders.ResultsOverall, 24 129 patients treated with TKIs were matched with 24 129 patients who did not receive TKIs (24 215 [50.18%] were female; and the mean [SD] age was 66.93 [12.37] years). Compared with those not receiving TKIs, the TKI group presented with a significantly lower hazard ratio (HR) of all-cause death (adjusted HR, 0.76; 95% CI, 0.75-0.78;P< .001), and the reason for death was primarily cancer. In contrast, the HR of MACCEs significantly increased (subdistribution HR, 1.22; 95% CI, 1.16-1.29;P< .001) in the TKI group. Furthermore, afatinib use was associated with a significantly reduced risk of death among patients receiving various TKIs (adjusted HR, 0.90; 95% CI, 0.85-0.94;P< .001) compared with those receiving erlotinib and gefitinib, although the outcomes of MACCEs were similar between the 2 groups.Conclusions and RelevanceIn this cohort study of patients with NSCLC, TKI use was associated with reduced HRs of cancer-related death but increased HRs of MACCEs. These findings suggest the importance of close monitoring of cardiovascular problems in individuals receiving TKIs.