BACKGROUND: Dyslipidemia is a known risk factor for cardiovascular (CV) events. The aim of the study was to assess lipid profiles and their impact on CV risk changes in a large patient cohort 5 years after Roux-en-Y gastric bypass (RYGB). METHODS: All patients who underwent primary RYGB for severe obesity in our two hospitals between January 1999 and December 2009 were included. The Framingham risk score was used. RESULTS: One thousand and forty-eight patients were included, 791 women and 257 men. Five-year complete lipid profile was available for 77% of patients. At 5 years, mean body mass index (BMI) decreased from 45.7 ± 6 to 31 ± 5.8 kg/m (p < 0.001), excess BMI loss (EBMIL) was 72.35 ± 22%, and total body weight loss (TWL) 31.5 ± 9%. Lipid values improved significantly. Total- and LDL-cholesterol levels dropped at 1 year from 5.4 to 4.48 mmol/L and 3.2 to 2.41 mmol/L, respectively, and slightly increased thereafter. Triglyceride levels dropped from 2 to 1.17 mmol/L at 1 year and remained unchanged. HDL levels rose continuously from 1.27 to 1.77 mmol/L at 5 years. Lipid profile improved more in patients with greater weight loss (%EBMIL ≥ 50 or %TWL ≥ 25%). Assuming that all patients were non-smokers and other baseline risk factors (hypertension, diabetes) remained unchanged at 5 years, the amelioration of the lipid profile itself yielded to a 27% reduction of CV risk (p < 0.001). CONCLUSIONS: RYGB results in sustained excess weight loss and in amelioration of the lipid profile from the first to fifth postoperative year. This improvement translates into significantly lower CV risk from the first year after surgery.