The present study addresses factors that contributed to explaining the variance in health-related quality of life (HRQOL) one year after myocardial infarction, considering both illness-related and health-promoting factors. The aim was to elucidate the influence of depression, fatigue, optimism and sense of coherence on HRQOL. The sample consisted of 95 persons who had been treated for myocardial infarction. Correlation and multiple regression analyses were performed. The results showed that depression, fatigue, optimism and sense of coherence variables were all correlated with both the physical and the mental dimensions of HRQOL. In two multiple regression analyses where the physical component score (PCS) and the mental component score (MCS) were the criterion variables, fatigue contributed to the explained variance in the PCS (p< 0.001), and both depression (p< 0.01) and fatigue (p< 0.01) contributed to explained the variance in the MCS, after controlling for age and gender. To conclude, fatigue was the most significant variable associated with HRQOL, which was interpreted as having the following clinical implication: When a person suffers from post-myocardial infarction fatigue, this must be addressed first. Clearly, it is time to take the problems of patients who suffer from post-myocardial infarction fatigue seriously. It is of vital importance to develop and evaluate fatigue relief strategies in cardiovascular nursing and to test them in interventional studies. This does not exclude investing in health-promoting factors, e.g. sense of coherence, in coronary care interventions. Intervention strategies focusing on both illness-related and salutogentic factors may be optimal. This is a question for further research.