OnabotulinumtoxinA (Ona A; Botox) powder for intramuscular injection solution is a neuromuscular paralytic agent derived from the fermentation of Clostridium botulinum type A and is one of several immunologically distinct serotypes of botulinum neurotoxin. It is indicated for the prophylaxis of headaches in adults with chronic migraine (CM) who have headaches that occur at least 15 days per month and last four hours a day or longer. Ona A is administered as a minimum of 31 injections and a maximum of 39 injections of five Allergan units (U) per injection to the head and neck (total: 155 U to 195 U per administration). The recommended retreatment schedule is every 12 weeks. Ona A is available in 50 U, 100 U, and 200 U vial sizes, at a cost of $178.50, $357.00, and $714.00 per vial, respectively ($3.57 per U). CADTH Canadian Drug Expert Committee previously reviewed Ona A in 2014 for CM and provided a do-not-list recommendation due to significant limitations of the underlying clinical evidence. The manufacturer submitted a cost-utility analysis for this resubmission that was similar to the initial submission in 2014. In the current submission, the manufacturer compared Ona A with best supportive care (BSC) for the prophylaxis of headaches in adults with CM over a three-year time horizon. The manufacturer also compared Ona A with topiramate in a pairwise scenario analysis to account for changes in clinical practice since the original submission. The Markov model in the resubmission attempted to address some of the previous limitations identified by CADTH by considering additional health care resource use and costs, and added health states to model headache frequency changes in patients who discontinue treatment. The manufacturer modelled 13 health states: six headache frequency health states (0 to 3, 4 to 9, 10 to 14, 15 to 19, 20 to 23, and 24 to 28 headache days per month [HDPM]) for each treatment status (i.e., on treatment or discontinued treatment due to treatment failure) and a death state. Patients entered the model in the various health states based on headache frequency distribution from a pooled analysis of the PREEMPT trials, and transitioned between states every 12 weeks. Similar to the original submission, efficacy and discontinuation data from the PREEMPT trials were pooled and used to inform transition probability for Ona A and BSC; placebo was used as a proxy for BSC. The manufacturer modelled response-based discontinuation based on current clinical practice, in which patients who do not experience a reduction of at least 50% in headache frequency after the initial 24 weeks discontinue treatment. Patients discontinuing Ona A or BSC were assumed to be treated with BSC (patients treated with BSC effectively did not discontinue). The manufacturer reported that Ona A was associated with an additional cost of $3,430 and generated an additional 0.10 quality-adjusted life-years (QALYs) compared with BSC, resulting in an incremental cost-utility ratio (ICUR) of $34,407 per QALY. At a willingness-to-pay threshold of $50,000 per QALY, the manufacturer reported that Ona A was associated with a 64% probability of being the optimal intervention compared with BSC.