Prophylactic cranial irradiation (PCI) has been demonstrated to significantly reduce the incidence of brain relapse from limited disease small-cell lung cancer (LD SCLC), but concerns about neurologic toxicity remain. The purpose of this report was to update a phase II institutional trial that explored the impact of twice-daily PCI on neurologic toxicity as well as outcome for this group of patients. All eligible subjects had documented complete response to induction chemotherapy and consolidative chest irradiation. The whole brain was treated with twice-daily fractions of 1.5 Gy with megavoltage irradiation to an approximate total dose of 30.0-36.0 Gy. Although not devised as a randomized study, approximately half of the eligible patients declined the protocol enrollment of their own volition and were retrospectively evaluated as a "historical" control group regarding the incidence of brain metastases. Fifteen patients accepted twice-daily PCI, with 12 deferring treatment. Median follow-up was 20 months. Disease-free survival at 2 years was 54% with twice-daily PCI versus 0% without any PCI (p = 0.013). Overall survival at 2 years was 62% with twice-daily PCI versus 23% without PCI (p = 0.032). No statistically significant neurologic deterioration was detected in the PCI group posttreatment. Thus, twice-daily PCI should be considered for patients with LD SCLC who achieve a complete response to chemoirradiation. A multi-institutional randomized trial would be necessary before making definitive recommendations.