Abstract This study evaluated the association between ultra-processed foods (UPF) on serum IL-6 and to investigate the mediation role of adiposity. Participants were 524 adults from the EPITeen Cohort (Porto, Portugal) and 2888 participants from the 1982 Pelotas Birth Cohort (Pelotas, Brazil). Dietary intake was collected using FFQ when participants were 21 years of age in the EPITeen and 23 years in the Pelotas Cohort. Serum IL-6 and body fat mass were evaluated when participants were 27 and 30 years old in the EPITeen and Pelotas, respectively. Generalised linear models were fitted to test main associations. Mediation of body fat mass was estimated using G-computation. After adjustment for socio-economic and behaviour variables, among females from the EPITeen, the concentration of IL-6 (pg/ml) increased with increasing intake of UPF from 1·31 (95 % CI 0·95, 1·82) in the first UPF quartile to 2·20 (95 % CI 1·60, 3·01) and 2·64 (95 % CI 1·89, 3·69) for the third and fourth UPF quartiles, respectively. A similar result was found among males in the Pelotas Cohort, IL-6 increased from 1·40 (95 % CI 1·32, 1·49) in the first UPF quartile to 1·50 (95 % CI 1·41, 1·59) and 1·59 (95 % CI 1·49, 1·70) in the two highest UPF quartiles. The P-value for the linear trend was < 0·01 in both findings. The indirect effect through fat mass was NS. Our findings suggest that the consumption of UPF was associated with an increase in IL-6 concentration; however, this association was not explained by adiposity.