ObjectiveWe assessed ultra‐processed food (UPF) intake and SLE incidence within the prospective Nurses’ Health Study cohorts.Methods204,175 women were followed, NHS: 1984 ‐ 2016; NHSII: 1991 ‐ 2017. Semi‐quantitative food frequency questionnaires were completed every 2‐4 years. UPF intake was determined as per the Nova classification. Nurses self‐reported new doctor‐diagnosed SLE, confirmed by medical records. Time‐varying Cox regressions estimated hazard ratios (HR, 95% confidence intervals) for incident SLE and SLE by anti‐double stranded DNA antibody (dsDNA) at diagnosis, according to cumulatively‐updated daily: a) UPF servings, b) total intake (gms + mls), and c) % total intake. Analyses adjusted for age, race, cohort, caloric and alcohol intakes, household income, smoking, body mass index (BMI), physical activity, menarchal age, and oral contraceptive use. We tested for interaction with BMI and examined UPF categories.ResultsMean baseline age was ~50 years (NHS) and ~36 years (NHSII); 93% self‐reported White race. 212 incident SLE cases were identified. SLE risk was higher in 3rd vs. 1st UPF tertile (servings/day pooled multivariable [MV] HR 1.56 (1.04‐2.32); p trend 0.03). Results were stronger for dsDNA+ SLE (servings/day pooled MV HR 2.05 (1.15‐3.65); p trend 0.01), and for absolute (servings or total) than % total intake. Sugar/artificially‐sweetened beverages were associated with SLE risk (3rd vs. 1st tertile MV HR 1.45 (1.01‐2.09). No BMI interactions were observed.ConclusionHigher cumulative‐average daily UPF intake was associated with >50% increased SLE risk, and with doubled risk for anti‐dsDNA+ SLE. Many deleterious effects on systemic inflammation and immunity are postulated.