Chronic kidney disease (CKD) is a risk factor for cardiovascular disease (CVD), although shared risk factors may mediate much of the association. CKD and CVD were related in the setting of specific CVD risk factors, and whether more advanced CKD was a CVD risk equivalent was determined. The Framingham Heart Study original cohort (n = 2,471, mean age 68 years, 58.9% women) was studied. Glomerular filtration rate was estimated (eGFR) using the simplified Modification of Diet in Renal Disease Study equation. CKD was defined as eGFR <59 (women) and <64 ml/min/1.73 m(2) (men), and stage 3b CKD was defined as eGFR of 30 to 44 (women) and 30 to 50 ml/min/1.73 m(2) (men). Cox proportional hazard models adjusting for CVD risk factors were used to relate CKD to CVD. Effect modification by CVD risk factors was tested for. Overall, 23.2% of the study sample had CKD (n = 574, mean eGFR 50 ml/min/1.73 m(2)) and 5.3% had stage 3b CKD (n = 131, mean eGFR 42 ml/min/1.73 m(2)). In multivariable models (mean follow-up 16 years), stage 3 CKD was marginally associated with CVD (hazard ratio [HR] 1.17, 95% confidence interval [CI] 0.99 to 1.38, p = 0.06), whereas stage 3b CKD was associated with CVD (HR 1.41, 95% CI 1.05 to 1.91, p = 0.02). Testing CVD risk equivalency, the risk of CVD for stage 3b CKD in subjects with previous CVD was significantly lower compared with subjects with previous CVD and no stage 3b CKD (age- and sex-adjusted HR for CVD 0.66, 95% CI 0.47 to 0.91, p = 0.01). Low high-density lipoprotein cholesterol modified the association between CKD and CVD (p = 0.004 for interaction). Stage 3b CKD was associated with CVD, but was not a CVD risk equivalent. In conclusion, CVD risk in the setting of CKD is higher in the setting of low high-density lipoprotein cholesterol.