Abstract: Objective Our study aimed to compare the effect of prophylactic cranial irradiation (PCI) or temozolomide (TMZ) in preventing brain metastases from small cell lung cancer and analyze their safety. Methods This trial recruited 52 patients in Chinese PLA General Hospital from Jan 2008 to Dec 2014. All patients were divided into PCI group(26) and TMZ group(26). In PCI group, patients received 25 Gy/10 F prophylactic cranial irradiation after first-line therapy, while in TMZ group patients received oral TMZ (100-150 mg/m²; d1-d5/28 d). One year brain metastases positive rate, cranial-progression-free survival, overall survival and progression free survival were analyzed, and adverse reactions were recorded. Results There were no significant difference between PCI group and TMZ group in 1 year brain metastases positive rate (19.23% vs 30.77%, P > 0.05), cranial-progression-free survival (16 months vs 15 months, P > 0.05), PFS (7 months vs 8 months, P > 0.05) and OS (25 months vs 18 months, P > 0.05). Acute adverse events in PCI group were dizziness and nausea, and some patients had long-term adverse reactions in nervous system. Patients received temozolomide had moderate hematologic toxicities and gastrointestinal adverse reactions, and can be tolerated. Conclusion Temozolomide is well tolerated and as good as traditional PCI in preventing brain metastases. Though temozolomide was inferior to PCI in prolonging OS, there was no statistically significant difference.