In female subjects, ageing and the menopausal transition contribute to a rapid increase of metabolic and cardiac risk factors. Exercise may be an option to positively impact various risk factors prone to severe metabolic and cardiac diseases and events. This study was conducted to determine the long-term effect of a multipurpose exercise program on metabolic and cardiac risk scores in postmenopausal women. 137 osteopenic Caucasian females (55.4 ± 3.2 yrs), 1–8 years postmenopausal, were included in the study. Eighty-six subjects joined the exercise group (EG) and performed an intense multipurpose exercise program which was carefully supervised during the 12-year period, while 51 females maintained their habitual physical activity (CG). Main outcome measures were 10-year coronary heart disease risk (10 y CHD risk), metabolic syndrome Z-score (MetS Index), and 10-year myocardial infarction risk (10 y hard CHD risk). Significant between-group differences all in favor of the EG were determined for 10 y-CHD risk (EG: 2.65±2.09% versus CG: 5.40±3.30%; P=0.001), MetS-Index (EG: −0.42±1.03% versus CG: 1.61±1.88; P=0.001), and 10 y-hard-CHD risk (EG: 2.06±1.17% versus CG: 3.26±1.31%; P=0.001). Although the nonrandomized design may prevent definite evidence, the intense multi-purpose exercise program determined the long-term efficacy and feasibility of an exercise program to significantly impact metabolic and cardiac risk scores in postmenopausal women. This trial is registered with ClinicalTrials.gov NCT01177761.