Background: Little is known about the impact of interventions targeting chronic stress levels on clinical outcomes among myocardial infarction (MI) patients with increased levels of stress. Objectives: To examine the impact of the addition of brief strategic therapy (BST) to usual care (UC) on clinical outcomes in first MI patients with increased levels of stress. Design: Eighty-one patients were randomly assigned to BST in conjunction with UC (medical treatment, risk factor information, and guidance on unhealthy behavior change) or to UC. Methods: The outcome measures were scores on the Perceived Stress Scale, reinfarction and cardiac mortality rates, and scores on the Health Survey. Measures were taken before, post-treatment, and at two follow-ups. Results: Patients subjected to BST showed reduced perceived stress at post-treatment and maintained decreased levels at follow-ups. At 1-year follow-up, they had a lower rate of non-fatal reinfarction, and at 2.5-year follow-up, they had a lower rate of fatal reinfarction. Their mental and physical health was improved at post-treatment and this was sustained at follow-ups. Conclusion: The addition of BST to UC favorably influences the disease course after MI in patients with increased levels of stress.