Prophylactic cerebral irradiation (PCI) reduces the rate of brain metastasis and improves the prognosis of patients with small cell lung cancer (SCLC), but little is known about the effect of PCI on second-line chemotherapy in patients with relapsed sensitive SCLC. This retrospective cohort study included a total of 164 patients with relapsed sensitive SCLC, 20 of whom were administered temozolomide (TMZ). Categorical clinical variables were compared between subgroups with the chi-square test or Fisher's exact test, continuous clinical variables were compared with the t-test or one-way ANOVA, and the impact on overall survival (OS) was assessed using Kaplan-Meier analysis with the log-rank test. In general, TMZ prolonged the OS of patients with SCLC with brain metastasis from 12.0 to 19.0 months [P=0.0109, hazard ratio (HR): 0.4789, 95% CI: 0.2470-0.9287]. Furthermore, the administration of PCI improved the effects of TMZ on patients with SCLC with brain metastasis, with an increase in OS from 16.0 to 36.5 months (P=0.0017, HR: 3.634, 95% CI: 1.083-12.20); additionally, no difference was observed on the basis of the history of chemotherapy or state of brain metastasis. For the local response evaluation, the overall response rate reached 75.0% for both brain metastasis and extracranial lesions in the two-cycle evaluation, remained at 30.0 and 25.0% in the four-cycle and more-cycle evaluations, respectively, and was minimally influenced by the history of chemotherapy or PCI. In conclusion, the results of this study suggest that PCI may be valuable for patients with relapsed sensitive SCLC with brain metastasis who are receiving TMZ treatment, and it may also serve as an effective regimen to prevent local progression of extracranial lesions; however, more evidence is needed.