IMPORTANCE Triptans are contraindicated in patients with ischemic heart disease or previous myocardial infarction, and caution is advised when prescribing these drugs to patients with vascular risk factors. However, controlled observational studies have either shown no association or an apparent lower risk, possibly owing to a channeling of triptans to individuals at low risk of cardiovascular outcomes, and it remains unclear whether avoiding triptan treatment for these patients is meaningful. OBJECTIVE To establish whether an association between triptans and ischemic events could be demonstrated using a self-controlled design because this type of design is robust to the previously mentioned type of confounding. DESIGN, SETTING, AND PARTICIPANTS All people in nationwide Danish registries who were initiating triptans and all the ischemic events that they experienced were identified. A case-crossover design was used to estimate odds ratios (OR) for associations between first-ever triptan use and ischemic outcomes, comparing triptan exposure in the 2-week period up to the event with four 2-week reference periods. Data were obtained for the period January 1995 to August 2022. Included from the population of Denmark were individuals redeeming a prescription for any triptan and experiencing at least 1 of 3 predefined ischemic outcomes. No one was excluded. EXPOSURE Initiation of any triptan. MAIN OUTCOMES AND MEASURES Acute myocardial infarction, ischemic stroke, or nonspecified stroke. RESULTS Identified were a total of 429 612 individuals (median [IQR] age, 38 [28-48] years; 325 687 female [75.8%]) who redeemed a first prescription for a triptan in the study period. Of these patients, 11 (0.003%) had a myocardial infarction with the first triptan prescription in either a focal or referent window (odds ratio [OR], 3.3; 95% CI, 1.0-10.9), 18 (0.004%) had ischemic stroke (OR, 3.2; 95% CI, 1.3-8.1), and 35 (0.008%) had ischemic/nonspecified stroke (OR, 3.0; 95% CI, 1.5-5.9). Case patients had a median age of approximately 60 years and had a high-risk cardiovascular profile. CONCLUSIONS AND RELEVANCE Results of this case-crossover study suggest that triptan initiation was associated with higher risk of ischemic stroke and myocardial infarction. For the individual patient with low background cardiovascular risk, the risk of an ischemic event after triptan initiation was very low.