Background <p>Prophylactic cranial irradiation (PCI) remains a contentious therapeutic approach in small-cell lung cancer (SCLC) despite its established efficacy in reducing brain metastases. The debate persists particularly in the context of modern imaging techniques like brain MRI.</p> Methods <p>This retrospective study examined the survival outcomes associated with PCI in surgically resected SCLC patients who underwent pre-PCI brain MRI at a Chinese cancer center. A total of 309 patients were initially screened, with 110 meeting inclusion criteria after applying rigorous exclusion criteria based on a decade-long dataset. Among them, 77 patients underwent molecular subtyping based on immunohistochemistry (IHC). Clinical and pathological features, along with survival outcomes, were compared between the PCI and observation groups.</p> Results <p>Among the final cohort, 58 patients received PCI while 52 were in the observation group. The PCI group exhibited significantly prolonged overall survival compared to the observation group (HR = 0.368, 95% CI 0.154–0.882, <i>P</i> = 0.0249) after adjusting for baseline imbalances using inverse probability of treatment weighting Subgroup analyses indicated notable survival benefits in male patients, those ≤ 65 years old, and individuals with pathological N0 disease. Compared to subtypes P (5.2%) and Y (11.7%), molecular subtyping indicates a higher prevalence of subtypes A (42.8%) and N (40.3%). Neuroendocrine subtypes (A and N) tend to have poorer prognoses and could obtained overall survival benefits from PCI. (HR = 0.276, 95% CI 0.091–0.839, <i>P</i> = 0.015).</p> Conclusions <p>This study supporting the use of PCI in surgically resected SCLC patients with pre-PCI brain MRI evaluation, demonstrating a significant survival advantage. Molecular subtyping through IHC may help identify SCLC patients who can benefit from PCI.</p>