Objective: Acute myocardial infarction (MI) has significant and detrimental effects on the lifestyles of the patients. It has been shown that quality of life (QoL) in patients with MI is impaired in every aspect. This study aims to evaluate the impact of depression and physical comorbidity on QoL in Turkish patients with acute first MI. Method: This multi-center cross-sectional study was carried out in 15 centers with 998 patients hospitalized for acute first MI. For detection of depression, Beck Depression Inventory (BDI) was used. For evaluation of QoL, World Health Organization Quality of Life Questionnaire (WHOQOL) was applied. Results: The mean age of the patients was 57.5 +/- 10.1 years and 79.2 % (n = 792) of the patients were men. Patients with comorbid depression (BDI >= 10) and comorbid medical conditions, and female patients had significantly lower scores in every domain of WHOQOL. In the regression analysis model, female gender, low education, comorbid medical conditions, especially comorbid hypertension, and BDI score were found to have a significant effect on the domains of WHOQOL. Conclusions: Female patients are more prone to impairment in quality of life after myocardial infarction. Both comorbid medical conditions and depression have a significant impact on the impairment of QoL in Turkish patients with acute MI. In order to improve the subjective wellbeing of post MI patients, both psychiatric and physical comorbidities must be detected and managed even in the short term.