Objective To observe the clinical efficacy and safety of three-dimensional conformaltherapy combined with icotinib or erlotinib in elderly and advanced lung adenocarcinoma patients with EGFR mutations and brain metastases. Methods Seventy-six elderly and advanced lung adenocarcinoma patients with EGFR mutations and brain metastases treated in our departments between November 2011 and November 2013 were randomly divided into two groups. Thirty-eight patients in treatment group received three-dimensional conformal radiation including primary tumors and metastases combined with icotinib (125mg, tid, po), and the dose for pulmonary primary tumors and lung metastases was 36-60Gy (2Gy/d, 5d/week), and for brain metastases the dose of whole brain radiotherapy was 30-40Gy (2Gy/d, 5d/week), then increased dose of IMRT was 10-20Gy (2Gy/d, 5d/week). Thirty-eight ones in the control group were treated with the same radiation regimen and erlotinib (150mg, qd, po). The efficacy and toxicity were evaluated after two cycles. Results The efficacy and toxicity could be evaluated in the 78 cases. The overall response rates were 63.2% and 57.9%, and the median progression free survival (PFS) was 9.9 and 9.0 months. Subgroup analysis showed that PFS in the two groups with different EGFR mutations was 11.2 and 10.6 months (19 exon deletion), 8.7 and 7.9 months (21 exon mutation), respectively, without significant difference (P>0.05). The most common toxicities of the two groups were rash, leukopenia, diarrhea and hepatic injury, which could be tolerated, with no significant difference (P>0.05). Conclusion Three-dimensional conformal therapy combined with icotinib or erlotinib in elderly and advanced lung adenocarcinoma patients with EGFR mutations and brain metastases has similar outcome and tolerance, thus being worthy of clinical application. [ABSTRACT FROM AUTHOR]