Good cardiorespiratory fitness has been found to protect against cardiovascular diseases and type 2 diabetes. The purpose of this study was to investigate determinants of directly measured cardiorespiratory fitness (maximal oxygen uptake [VO2max]), including age, body composition, prevalent diseases, cardiovascular and pulmonary functions, biochemical factors, physical activity, nutrition, smoking, and alcohol consumption, in a population-based study of 936 men 42 to 60 years of age. Variables that had the strongest direct associations with VO2max (milliliters per minute) in a linear multivariate step-up regression model were body weight, heart rate at maximal exercise, mean intensity and frequency of conditioning physical activity, intake of carbohydrates, blood hemoglobin, and forced expiratory volume in 1 second. The strongest inverse associations with VO2max were heart rate at rest, age, fasting serum insulin, waist-to-hip ratio, coronary heart disease, and asthma. This model accounted for 67% of the variation of VO2max. In conclusion, mean intensity, frequency, and duration of conditioning physical activity were associated directly with VO2max. However, measurements of the function of pulmonary and cardiovascular systems, carbohydrate intake, and body composition were powerful determinants of cardiorespiratory fitness, especially in older middle-aged men.