Background: As the standard therapy for non-small cell lung cancer (NSCLC) patients expressing epidermal growth factor receptor (EGFR) mutations, EGFR tyrosine kinase inhibitors (EGFR-TKIs) possess advanced potency and survival outcomes in clinical trials. However, little is known for stomatitis as a potential adverse event. This study aimed to assess the risk of stomatitis among patients initiating different EGFR-targeted therapy for NSCLC in a real-world study. Methods: Patients diagnosed with NSCLC and newly initiated EGFR-targeted therapy between 2008 and 2023 were included from 92 healthcare organizations across the U.S., then matched to non-users via propensity scores on age, comorbidities, metastatic status, and previous history of anticancer therapies. The primary outcome, stomatitis, was retrieved by ICD-9 or ICD-10 codes. The risk of stomatitis in association with EGFR-TKI was evaluated using regression models to obtain the odds ratio (OR) with 95% confidence intervals (CIs). Subgroup analyses were conducted to identify the EGFR-TKI agents that were associated with the risk of stomatitis. Results: A total of 22,225 EGFR-TKI initiators were included, including 719 on gefitinib, 16,404 on erlotinib, 1,864 on afatinib, and 5,300 on osimertinib. EGFR-TKIs initiators presented with a significantly increased risk of stomatitis compared to non-users (n= 445 vs 367; OR=1.22; 95% CI=1.058-1.399). Among all EGFR-TKIs, erlotinib (n=316; OR=1.56; 95% CI=1.394-1.739), afatinib (n=81; OR=3.49; 95% CI=2.794-4.365), and osimertinib (n=95; OR=1.40; 95% CI=1.139-1.711) were significantly associated with an increased risk of stomatitis before propensity score matching. The risk of EGFR-TKI-associated stomatitis in those treated with afatinib was validated after propensity score matching (OR=2.23; 95% CI=1.528-3.393). Conclusions: The present study demonstrated a significantly high risk of stomatitis in relation to EGFR-targeted therapy for NSCLC. Multidisciplinary care involving oral medicine specialists and dentists is needed for patients with lung cancer.