The objective of this work was to develop and test a questionnaire to measure health-related quality of life for patients after myocardial infarction (MI). In a cross-sectional survey, 63 patients identified the most frequent and important problems following acute myocardial infarction. The Quality of Life after Myocardial Infarction (QLMI) instrument was developed on the basis of these most frequent and important problems. The QLMI was administered, along with instruments measuring health utilities, social function, and emotional function, in a randomized trial of rehabilitation versus conventional care. The most frequent and important problems fell into areas of symptoms, restriction, confidence, self-esteem, and emotions, each of which is represented in the 26-item QLMI. Effect sizes of the overall QLMI in differentiating between rehabilitation and control groups (0.35), and in detecting improvement over 12 months (1.22) were comparable or larger than any other instrument. The Pearson's correlation coefficient between QLMI administered at 8 and 12 months following AMI varied between 0.75 and 0.87 for the five domains and the overall score. We found substantial correlations of the QLMI with other measures with moderate concordance with predictions about how the instrument should behave if it is a valid measure of health-related quality of life. The QLMI demonstrates a high degree of reliability, and is more responsive than other questionnaires. Relations between the QLMI and other measures provide moderate to strong evidence of its validity in discriminating between patients following AMI according to their health-related quality of life, and in measuring changes in health-related quality of life over time.