BACKGROUND: How weight change affects the metabolic syndrome (MS) and its parameters is unknown, particularly, in a leaner European population such as the French prospective D.E.S.I.R. cohort. METHODS: In 3770 D.E.S.I.R. participants (sex ratio=1) averaging 47.5 years (range 30-64), with measured weight and MS parameters at baseline (D0) and at 6 year follow-up (D6), we assessed this relationship across five weight-change classes, using stable weight as the referent group (-2 to +2 kg). We used analysis-of-covariance to assess changes in each MS parameter and logistic regression to assess incident MS, according to the National Cholesterol Education Program (NCEP). We also assessed weight-change effect on MS status between D0 and D6. RESULTS: At D0, average weight was 68.4 kg (SD 12.3); BMI was 24.8 kg/m2 (SD 3.5). From D0-D6, the cohort gained a mean 2.1 kg (median 2.0; SD 4.4). After adjustment for age and D0 weight, there was a strong linear relationship with weight change and worsening of the following MS parameters at D6: fasting insulin, waist girth, fasting glucose, fasting triglycerides, HDL cholesterol, and systolic and diastolic blood pressure (P<0.0001). After age adjustment, for every kilogram gained over 6 years, risk of developing the NCEP Syndrome increased 22% (OR 1.22; 95% CI 1.18-1.25). NCEP-MS was incident in 3% of those with stable weight compared with 21% among those gaining >9 kg; 10% of those who lost >2 kg reverted to non-NCEP-MS. CONCLUSIONS: All continuous MS measures are linearly related to weight change, and MS can resolve with modest weight loss, underscoring the importance of maintaining lifelong normal weight.