Persistent organic pollutants (POPs) are well-known ubiquitous environmental chemicals which have been related to adverse health outcomes, including cardiovascular disease (CVD). The purpose of this study was to evaluate POPs burden, and its determinants, in a population at high risk of suffering CVD enrolled in the PREDIMED Study (Spanish acronym for PREvention by means of MEDiterranean Diet). This cohort was formed by 343 participants (55–80 y.o.), which were selected for a preventive nutritional intervention for CVD based on the Mediterranean Diet. Relevant information on demographic, behavioral, dietary, and socioeconomic characteristics was obtained from each participant through a specific questionnaire, and their anthropometric and clinical measurements were recorded. In addition, the levels of 35 POPs were determined in serum samples taken before the beginning of the nutritional intervention. All the samples showed detectable levels of, at least, one POP, being DDT-derivatives and marker-PCBs the most frequently detected compounds. Our results showed that people at high risk for CVD showed a higher level of contamination by POPs as compared to other studies done in cohorts of Western people at no special risk of CVD. Although educational level seems to be a relevant determinant for POPs burden in our population, the main determining factor seems to be the diet. Thus, while the intake of food of animal origin was significantly associated with levels of PCBs, especially in men, the intake of vegetal-origin food was positively related to levels of organochlorine pesticides, indicating a different dietary source for these two groups of chemicals. Our results showing that subjects at high risk for cardiovascular disease present elevated POPs burden might have a relevant public health impact given the generalized and difficult to avoid exposure to POPs and the elevated worldwide frequency of the CVD.