The aim of this study was to determine the trends of cardiovascular risk factor prevalence between 1988/9 and 2008/9 in the 25-74-year-old population in an area of Southern Italy. We compared three cross-sectional studies conducted in random population samples, in 1988/9, 1998/9, and 2008/9 in Salerno, Italy. The methodology of data collection (lipid profile, systolic and diastolic blood pressure, glycaemia, and smoking) and conducting tests which the population underwent during the three phases was standardized and comparable. Prevalence of diabetes, hypertension, hypercholesterolemia, and smoking was calculated and standardized for age. A total of 3491 subjects were included. From 1988/9 to 2008/9, in males, the prevalence of all four risk factors was reduced. In women, there was a clear reduction of hypertension, a similar prevalence of hypercholesterolemia, and an increase of smoking and diabetes. In the area of Salerno, our data confirm that the global prevalence of the major risk factors is decreasing in men, but their absolute values are still far from optimization. In women, diabetes and smoking showed a negative trend, therefore requiring targeted interventions. These data are now used as a base for executive targeted programs to improve prevention of cardiovascular disease in our community.