Many epidemiologic studies presently aim to evaluate the effect of risk factors on renal function. As direct measurement of renal function is cumbersome to perform, epidemiologic studies generally use an indirect estimate of renal function. The consequences of using different methods of renal function measurement in studies that evaluate the effect of cardiovascular risk factors on renal function were questioned. Data of the 8592 Prevention of Renal and Vascular End-stage Disease study participants, in whom the association was plotted between various cardiovascular risk factors and renal function measured either by creatinine clearance based on two 24-h urine collections or by the Cockcroft-Gault or Modification of Diet in Renal Disease formula were used. A repeated measurement analysis was used to compare the slopes of the linear regression lines of the risk factors and the different methods of renal function measurements. The relation between cardiovascular risk factors and renal function seems to be different when different methods for renal function are used. This was most pronounced for age, weight, and body mass index and less pronounced (but still statistical significant) for BP, cholesterol, and glucose. The relation between weight or body mass index and renal function showed completely different directions, depending on the renal function method used. In conclusion, the interpretation of the relation of cardiovascular risk factors and renal function is affected by the method selected to estimate renal function. For studying the relation of risk factors and renal function in large population studies, indirect estimates of renal function should be used with caution.