Background: Depression is a major public health concern worldwide and its association with metabolic syndrome (MetS) remains unclear. Thus, we prospectively examined the association between depression and the risk of MetS, according to different diagnosis criteria. Methods: This study included 9,237 participants of a Spanish dynamic prospective cohort of adult university graduates [mean (SD) age: 36.7 year (10.7)], initially free of any specific criterion of MetS, who were followed up for a median of 8.3 years. The exposure variables were medical diagnosis of depression at baseline or in the first 2-year follow-up questionnaire. The outcome variable was the incidence of MetS, assessed according to each of three different criteria proposed by: International Diabetes Federation (IDF); National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III); IDF/NCEP-ATP III (updated harmonizing definition). Multivariable-adjusted Relative Risks (RR) of new-onset MetS and their 95% Confidence Intervals (95% CI) were estimated, using Poisson regression models. Results: The cumulative incidences of MetS were 475 cases (IDF definition), 288 cases (NCEP-ATP III definition) and 492 cases (update harmonized definition). No association was observed between baseline depression and incidence of MetS, but the presence of depression after 2-years of follow-up was significantly associated with a higher risk of new-onset MetS, according to NCEP-ATP III definition (multivariable-adjusted RR, 2.46; 95% CI, 1.06-5.67). Limitations: Diagnosis of depression and MetS were self-reported. Conclusions: In this large prospective cohort of Spanish middle-aged adult university graduates, a direct association between depression and the risk of MetS according to NCEP-ATP III definition was found.