Objective To review and assess the quality of the available evidence on the cost-effectiveness of erlotinib in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Methods A systematic review was conducted to identify full-text original economic evaluations of erlotinib in the first-line treatment of advanced NSCLC written in English and published from the year 2000 onwards. Study characteristics and results were recorded and compared. The quality of the studies was assessed by the Quality of Health Economic Studies (QHES) questionnaire. Results Eleven out of 130 papers were chosen for this review. Comparative regimens consisted of a best supportive care, reverse strategy, bevacizumab, cisplatin plus pemetrexed, carboplatin plus gemcitabine or gefitinib. The methods most used in these studies were modeling and sensitivity analysis and cost-effectiveness analysis. All of the studies evaluated direct costs and used quality-adjusted life-year (QALY) and life-years gained (LYG) as outcome, with 3% and 3.5% discount rate. The studies assigned ICER that ranged from dominant to I 305,510.31/QALYandfromI 31,209.55/LYG to I 66,540.20/LYG.Basedonthewillingnesstopaythreshold,sevenstudiesconcludedthaterlotinibwascost-effective,twostudiesshowedthaterlotinibwascost-effectiveonspecificpatientswithcertainconditions,andtwostudiescomparingerlotinibwithreversestrategydidnotfindadifferenceincost-effectiveness.ThehighqualityofthesestudieswasconfirmedusingtheQHEStool:themeanscorewas75.77outof100(SD9.38).ConclusionMostofthesehigh-qualitystudiessuggestedthaterlotinibwascost-effectiveinthefirst-linetreatmentofadvancedNSCLC.