Two new agents have recently been licensed as maintenance therapy for advanced non-small-cell lung cancer (NSCLC) by the US Food and Drug Administration. This paper aims to systematically review the evidence from all available clinical trials of erlotinib and pemetrexed as maintenance therapy for advanced NSCLC. Systematic literature searches were performed in PUBMED, EMBASE and Cochrane databases. Abstracts presented at two conferences were also researched. The effects of erlotinib and pemetrexed on overall survival and progression-free survival were compared using an indirect treatment comparison method with placebo or observation as a common comparator. Five randomized controlled studies were included. Both interventions offered significant advantages for overall survival (OS) and progression-free survival (PFS) compared with placebo or observation. Using indirect comparison meta-analysis, the relative hazards ratio of pemetrexed compared with erlotinib for PFS was 0.71 (95% CI 0.60-0.85; p = 0.0001), suggested that pemetrexed was superior to erlotinib in terms of progression-free survival. Although relative hazards ratio for OS showed no significant difference between the two agents (HR 0.88; 95% CI 0.71-1.08, p = 0.22). There is evidence to suggest that maintenance treatment with erlotinib or pemetrexed has clinically relevant and statistically significant advantages over treatment with placebo or observation in patients with advanced NSCLC.