Abstract Background/Introduction The role of ultra-processed foods (UPF) on multimorbidity is currently unknown with limited research implying the existence of complex associations among the diverse UPF categories. Purpose The aim of the present work was to investigate the association of total and subgroup intake of UPF with cardiometabolic multimorbidity, after twenty years of observation, in a Mediterranean region. Methods In 2001-2002, n=3,042 free-of-cardiovascular disease (CVD) men and women from Attica, Greece, were recruited. Dietary assessment was based on a validated semi-quantitative food frequency questionnaire. The NOVA Food Classification system was used to assign the food products as UPF using a standard methodology. The food products assigned as UPF were further grouped as "bread and cereals", "spreads and sauces", "sweets and desserts", "artificially and sugar-sweetened beverages", "processed meat products" and "savory snacks". Cardiometabolic multimorbidity was defined as the co-occurrence of two cardiometabolic diseases i.e., type 2 diabetes and CVD within a 20-year follow-up period in a sample of n=1,846 participants with available data. Results The median consumption level of UPFs was 26.6 (16.3) servings/week contributing to around 40% of participants total daily energy intake. Over the 20–year follow–up period, n=231 cases of cardiometabolic multimorbidity were recorded. Ranking from 1st tertile (lower intake– 11.8 mean servings/week) to 2nd tertile (23.3 mean servings/week) and 3rd tertile (44.7 mean servings/week) regarding the consumption level of UPF, 20-year cardiometabolic multimorbidity was 9.5%, 13.4% and 14.7% respectively. Multi-adjusted analysis revealed that one standard deviation (SD) increase in UPF intake (servings/week) or in contribution of UPFs to total energy intake (% total energy intake) was associated with 26% [Odds ratio (OR)=1.26, 95% Confidence Interval (95%CI) (1.17–1.85)] and 29% higher risk of cardiometabolic multimorbidity [OR=1.29, 95%CI (1.08–1.69)]. Among UPF subgroups, only in case of artificial and sugar-sweetened beverages [OR=1.06, 95%CI (1.02–1.13)] as well as spreads and sauces [OR=1.06, 95%CI (1.02–1.13)] a positive association was observed. In case of breads and cereals an inverse association was observed [OR=0.95, 95%CI (0.92–0.98)]. In the rest categories even if a positive trend was observed (all ORs>1) significance was not reached (all p-values<0.05). Conclusion A dose-response relationship between UPF consumption and elevated risk of cardiometabolic multimorbidity was emerged. However, the diverse categorization of UPFs accompanied by the contradicting associations revealed herein among the different subcategories of UPFs could imply the need to return to the evaluation of foods more on the basis of their nutritional role and less on the basis of their degree of processing. The nation context accompanied by specific dietary habits should also be taken into consideration.