BACKGROUND: Patients with myocardial infarction with nonobstructive coronary arteries (MINOCA) or Takotsubo syndrome (TS) often suffer from poor mental health and low quality-of-life post event, with no current evidence-based treatments available. This study aimed to evaluate the effects of an internet-delivered cognitive behavioral therapy program on stress and anxiety symptoms in patients diagnosed with myocardial infarction with nonobstructive coronary arteries or TS. METHODS: A parallel, multicenter, randomized controlled trial with a wait-list control group was conducted. Patients with elevated symptoms of stress or anxiety were included (the 14-item perceived stress scale ≥25 or hospital anxiety and depression scale, anxiety subscale ≥8). The primary outcome was normalized stress and anxiety levels 10 to 12 weeks after randomization. Secondary outcomes included normalized stress and anxiety separately and symptoms as continuous measures. RESULTS: A total of 88 patients were randomized (treatment: 45, control: 43). The treatment group showed a greater, though not statistically significant proportion of normalized patients (odds ratio, 2.37 [95% CI, 0.88-6.38], P=0.09). Secondary analyses indicated treatment effects on anxiety normalization and on symptoms as continuous measures (effect sizes: d=0.44-0.67). There was also an interaction between treatment and diagnosis (TS versus non-TS), favoring a treatment effect in TS patients (P=0.016). CONCLUSIONS: The patient-tailored internet-delivered cognitive behavioral therapy program reduced stress and anxiety symptoms in patients with myocardial infarction with nonobstructive coronary arteries or TS and normalized anxiety symptoms in a greater proportion of treated patients than controls. Exploratory analyses indicated that patients with TS may experience greater benefit from the internet-delivered cognitive behavioral therapy intervention, but this warrants further research.