The aim of this study was to investigate whether melanoma impairs intrinsic heart function in mice and whether short-term voluntary running wheel exercise could reduce the possible negative effects. Additionally, we investigated whether changes in cell size, capillary density, calcium channel levels, metabolic enzyme activities or oxidative stress could explain the possible changes in heart function. Advanced melanoma has been shown to cause cardiac muscle wasting and influence heart function in vivo, we hypothesized that melanoma would also impair intrinsic heart function, which has not been investigated previously. We also hypothesized that voluntary short-term exercise could reduce the effects of melanoma on cardiac function since exercise training is known to improve cardiovascular function and reduce the negative effects of some cancers. Male mice were divided into untrained tumor-free group (control) and untrained melanoma group and trained melanoma group. The mice did voluntary running-wheel exercise until predetermined tumor size after which their hearts were isolated. The cardiac function was measured in retrograde perfusion at a constant pressure in multiple oxygen levels using Langendorff apparatus. The molecular and tissue level markers were measured afterwards. The melanoma animals were not cachectic as indicated lack of body weight loss. The rate of pressure production, pressure amplitude and rate of pressure decline were all significantly lower in the isolated hearts of the melanoma animals as compared to tumor-free animals. However, the heart function did not differ between the untrained and trained melanoma groups. Furthermore, there were no differences between the groups in the calcium channel levels, reactive oxygen species, catalase activity, lipid peroxidation or citrate synthase and lactate dehydrogenase activity. However, mice from both melanoma groups had significantly lower superoxide dismutase activity as compared to tumor-free animals, which might reduce the heart's ability to respond to possible changes in oxidative stress. Exercise trained animals had higher capillary density, but their cell size and heart weights did not significantly differ from the untrained groups. Running wheel exercise did not affect the final tumor growth either even though there was tendency at the beginning of the experiment that running wheel exercise could slow down the tumor growth. One reason for this could be that when melanoma proceeded, the mouse running activity reduced significantly. In conclusion, melanoma is an aggressive cancer that impairs intrinsic heart function even when no cachexia is present. The aggressiveness of melanoma also prevented the short-term voluntary exercise from alleviating the changes caused by melanoma. Future studies should combine the training to medical cancer treatment in order to estimate whether exercise training could be beneficial as adjunct therapy in melanoma treatment. © FASEB.