Background. Physical exercise exerts a positive effect on many chronic conditions, specifically lifestyle-related diseases such as overweight and obesity, type 2 diabetes mellitus (T2DM), cardiovascular conditions and osteoarthritis (OA). As a result of common risk factors, most of these patients present with multiple conditions. Exercise- and disease-related biomarkers, such as adipokines, are emerging tools in training supervision and regulation; however, their significance in subjects with multimorbidities is unknown. Subjects and Methods. To address this issue, adipokines leptin, adiponectin and resistin were assessed in a cohort of subjects with multimorbidities (n = 39) presenting with at least two of the abovementioned conditions or relevant risk factors before and after a six-month exercise and lifestyle intervention program (‘MultiPill-Exercise’), and correlated with training adaptation, namely changes in relative maximum oxygen uptake (V·O2max). Results. There was a significant negative correlation between baseline leptin concentrations and training effect for relativeV·O2max(after three months: rho = −0.54,p= 0.020 *; after six months: rho = −0.45,p= 0.013 *), with baseline leptin explaining 35% of the variance in delta relativeV·O2maxafter three months and 23% after six months. Conclusions. Leptin might be a suitable surrogate biomarker in the context of exercise-based lifestyle intervention programs in subjects with multimorbidity.