Introduction Anaplastic lymphoma kinase (ALK) targeting drugs provide an important option for advanced non-small cell lung cancer patients with this distinct tumor type; however, there is considerable uncertainty as to which drug provides the optimal value after crizotinib treatment. This study estimated the cost-utility of alectinib vs ceritinib from a US payer perspective. Methods A cost-utility model was developed using partition survival methods and three health states: progression-free (PF), post-progression (PP), and death. Survival data were derived from the key clinical trials (alectinib: NP28761 & NP28673, ceritinib: ASCEND I and II). Costs included drugs, adverse events, and supportive care. Utilities were based on trial data and the literature. One-way and probabilistic sensitivity analyses (PSA) were performed to assess parameter uncertainty. Results Treatment with alectinib vs ceritinib resulted in increases of 2.55 months in the PF state, 0.44 quality adjusted life-years (QALYs), and $13,868, yielding a mean cost/QALY of $31,180. In the PSA, alectinib had a 96% probability of being cost-effective at a willingness-to-pay of $100,000/QALY. Drivers of model results were drug costs and utilities in the PF health state. The ICER ranged from $10,600-$65,000 per QALY in scenario analyses, including a sub-group analysis limited to patients with prior chemotherapy and crizotinib treatment. Conclusions Treatment with alectinib in ALK + crizotinib-treated patients increased time progression-free and QALYs vs ceritinib. The marginal cost increase was driven by longer treatment durations with alectinib. This model demonstrates that alectinib may be considered a cost-effective treatment after progression on crizotinib.