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Prophylactic cranial irradiation (PCI) has proven to decrease the incidence of brain metastases (BMs), with a modest improvement in survival.The impact of PCI was evaluated in 184 patients treated with chemoradiotherapy. PCI was applied to patients with disease with partial and complete response only when cranial magnetic resonance imaging before and after primary treatment revealed no BMs. Correlation between PCI and overall survival (OS), BM-free survival (BMFS), and time to progression (TTP) was analyzed to describe survival within subgroups.Concurrent and sequential chemoradiotherapy was applied in 71 patients (39%) and 113 patients (61%), respectively. Seventy-one patients (39%) with partial and complete response were treated with PCI. Metachronous BMs were detected in 16 (23%) of 71 patients in the PCI group compared to 42 (37%) of 113 patients in the non-PCI group. Median BMFS in the PCI group was not reached; it was 23.6 months in the non-PCI group. Median OS and TTP were 26 months (range, 19.4-32.6 months) in the PCI group versus 14 months (range, 11.4-16.6 months) in patients without PCI whose disease responded to therapy versus 9 months in patients with disease that did not respond to therapy (P < .0001), and 27 versus 14.5 months (range, 9.0-19.9 months) versus 8.8 months (range, 7.7-9.9 months) (P < .0001) in the PCI group versus those with response without PCI versus those with nonresponse. The effect of PCI was independent of gender. On multivariate analysis, PCI was a variable correlating with OS (hazard ratio = 1.899; 95% confidence interval, 1.370-2.632; P < .0001) and TTP (hazard ratio = 2.164; 95% confidence interval, 1.371-3.415; P = .001) after adjustment for other prognostic factors.In real-life patients comprehensively staged with cranial magnetic resonance imaging, treatment response and PCI strongly correlated with prolonged OS, TTP, and BMFS.To evaluate the effect of prophylactic cranial irradiation (PCI) in patients with disease that responded to therapy, we reviewed 184 limited-disease small-cell lung cancer patients comprehensively staged by contrast-enhanced cranial magnetic resonance imaging. Treatment response and PCI strongly correlated with prolonged overall survival, time to progression, and brain metastasis–free survival.