This study aimed to analyze the cost-effectiveness of crizotinib versus ceritinib or alectinib as first-line-targeted drug therapy for anaplastic lymphoma kinase-positive advanced non-small cell lung cancer in China. The Markov model was used to simulate the medical cost and quality-adjusted life years (QALYs) of patients using crizotinib, ceritinib, or alectinib over a 10-year period by establishing three health states: progression-free, post-progression, and death. Randomized controlled clinical data were collected from the open-label, randomized phase 3 trials ALEX and ASCEND-4. Cost and utility values were derived from local charges and literature. Sensitivity analyses included one-way and probabilistic sensitivity analyses. Compared with patients who used crizotinib as first-line treatment, patients in the ceritinib and alectinib groups yielded an additional 1.32 and 3.30 QALYs with an incremental cost of $84,728.20 and $339,114.36, respectively. Thus, the incremental cost-effectiveness ratio (ICER) was $64,398.83 and $102,675.74 per QALY in the ceritinib and alectinib groups, respectively. Alectinib was estimated to be more effective (4.68 QALY) and more costly ($432,063.06) with an ICER of $128,019.42 per QALY compared with ceritinib (2.69 QALY and $177,676.90). Results were robust to deterministic and probabilistic sensitivity analyses. As a first-line treatment regimen, ceritinib and alectinib can extend the survival time of patients compared with crizotinib, but the medical cost also increases accordingly. According to the World Health Organization's three-percent GDP measurement, first-line treatment with Crizotinib is the most cost-effective. © 2019 Liu et al.