Introduction Physical activity is associated with improved fibrinolytic activity and reduced risk for cardiovascular disease. High levels of leptin and low levels of adiponectin, both adipocyte-derived hormones, or adipokines, are related to dysfibrinolysis and risk for cardiovascular disease. In this study, we explored if improved fibrinolytic activity during exercise could be linked to changes in leptin and adiponectin levels. Materials and methods Twenty healthy men (mean age 36 years) participated in a 14-day long skiing expedition in the Swedish mountains. They were randomly assigned to either a 40% or a 30% fat-based diet. Anthropometry, lipids, fibrinolytic activity (PAI-1 activity, tPA activity and mass) and adipokines (leptin and adiponectin) were measured before, during and six weeks after the expedition. Results PAI-1 activity and circulating levels of leptin decreased whereas levels of adiponectin increased during exercise. The fall in PAI-1 activity showed a strong linear association with changes in leptin and adiponectin levels ( p = 0.001 and p < 0.001, respectively). Changes in leptin and adiponectin levels were independent of decreasing waist circumference. However, the association between anthropometric measures and adipokines changed considerably during the expedition. Adiponectin was weakly and negatively associated with BMI at baseline. In contrast, there was a strong positive association between adiponectin and BMI after two weeks of exercise, whereas the association between leptin and BMI became less pronounced. In addition, increasing leptin and decreasing adiponectin levels were associated with increasing PAI-1 activity during the six weeks following the expedition. After six weeks of normal activity, fibrinolytic activity and hormone levels returned towards baseline levels. Conclusion Heavy exercise induced improved fibrinolytic activity, which was associated independently with changes in circulating levels of the adipocyte-derived hormones leptin and adiponectin. Improved fibrinolytic activity (and reduced risk for cardiovascular disease) related to physical activity could possibly be mediated by leptin and adiponectin.