<h3>Purpose/Objective(s)</h3> Despite advances in the treatment of NSCLC and SCLC, locoregional recurrences or second primary tumors after irradiation (RT) remain a therapeutic challenge due to the toxicity of re-RT and limited efficacy of systemic therapy alone. We evaluated safety and efficacy of definitive intent re-RT with intensity-modulated proton therapy (IMPT). <h3>Materials/Methods</h3> In this single institution retrospective cohort study, consecutive patients with biopsy-confirmed recurrent or second primary NSCLC or SCLC received IMPT re-RT (dose in GyE) after initial definitive intent photon RT (dose in Gy). Univariate associations between variables of interest were examined with ANOVA for categorical variables and Pearson correlation coefficient for continuous variables. Time-to-event variables were estimated using the Kaplan-Meier method and associations modeled by Cox proportional hazards model and log-rank test. <h3>Results</h3> We identified 22 patients with recurrent or second primary NSCLC (n=20) or SCLC (n=2) treated from April 2019 to May 2021. Median initial RT dose was 60 Gy (range 45-70 Gy) with 10 patients (45%) receiving immunotherapy after initial RT. Re-RT started median 28.2 mo (range 8.8-172.9 mo) after initial RT. The median age at re-RT was 71 (range 54-85) with median ECOG performance status 1 (range 0-2). One patient had an actionable mutation and 5 patients had PD-L1 >1%. Most patients had locally advanced recurrences with 50% rT3-4 (n=11) and 59% rN1-3 (n=13). Median re-RT dose was 60 GyE (range 44-60 GyE) frequently in 30 fractions (n=9) or 15 fractions (n=7). With re-RT, 8 patients (36%) received concurrent chemotherapy. Four patients (18%) had immunotherapy after re-RT. Re-RT median lung V20 GyE was 8% (range 2%-26%), lung mean dose was 5.3 GyE (range 0.9-13.9 GyE), heart mean dose was 2.5 GyE (range 0-24.4 GyE), and esophagus mean dose was 6.6 GyE (range 0.2-24.2 GyE). With median follow-up 7.4 months after completion of re-RT, 1-yr OS was 68%, 1-yr PFS was 45%, 1-yr DMFS was 60%, and 1-yr LC was 80%. Higher re-RT and initial RT mean lung doses were significantly associated with worse OS, and there was trend for worse OS among patients with re-RT doses below 50 GyE (Table). Two patients (9%) developed grade 3 toxicities, 1 patient had grade 2 toxicity (5%), and 5 patients (23%) had Grade 1 toxicities. No grade 4 or 5 toxicities were observed. No significant dosimetric correlates were identified with toxicity. <h3>Conclusion</h3> Definitive IMPT re-RT for NSCLC and SCLC can prolong disease control with limited toxicity, particularly in the modern era with routine use of PD-L1 inhibitors. However, careful patient selection and planning are needed for optimal outcomes.