Exploring new models of medical care requires evaluating the impact of new care strategies not only on physiological parameters but also on the quality of life of the patient. On the other hand the presence of anxiety together with depression requires further consideration when planning appropriate management strategies. The aim of this study was to examine the effectiveness of a home-based cardiac rehabilitation program incorporating an e-Health technology on health-related quality of life associated with symptoms of anxiety and depression in moderate-risk patients. A multicenter, randomized controlled clinical trial was designed to compare a traditional hospital based cardiac rehabilitation program (n = 38, 35 male) with a mixed home surveillance program where patients exercised at home with a remote electrocardiographic monitoring device (n = 33, 31 male). The Short Form-36 (SF-36) Health Survey and the Goldberg questionnaire were used to evaluate quality of life and the presence of symptoms of anxiety and depression respectively. The results of this study show that the type of cardiac rehabilitation program did not influence the improvement in quality of life (p = 0.854), but the presence of symptoms of anxiety and depression did (p = 0.001). Although both programs achieved a decrease in anxiety and depression symptoms and improved functional capacity (p ≤ 0.001), a significant interaction effect was found between the group with or without anxiety and depression symptoms and the type of program in the bodily pain dimension (p = 0.021). Trial registration: Retrospectively registered NCT02796404 (10/06/2016) in clinialtrials.gov.