Abstract Objective To investigate the association between intake of food additive preservatives and cancer incidence in a large prospective cohort. Design Prospective cohort. Setting French NutriNet-Santé cohort, 2009-23. Participants 105 260 participants (≥15 years) without prevalent cancer who completed at least two 24 hour dietary records at baseline. Main outcome measures Cumulative time dependent intake of preservatives, including those in industrial food brands, assessed using repeated 24 hour dietary records and evaluated through multiple composition databases and ad hoc laboratory assays in food products for the most frequently consumed additive-food pairs. Associations between intake of three categories of preservatives (defined as sex specific thirds if preservative was consumed by at least a third of participants, otherwise defined as non-consumers and lower or higher consumers separated by the sex specific median) and cancer incidence were characterised using multivariable proportional hazards Cox models adjusted for potential confounders. Results Mean age of participants was 42.0 years (standard deviation (SD 14.5) years), and 78.7% were women. 4226 participants received a diagnosis of incident cancer (mean follow-up 7.57 (SD 4.56) years), comprising 1208 breast, 508 prostate, 352 colorectal, and 2158 other cancers). Higher intakes of several preservatives were associated with higher cancer incidence: total non-antioxidants with overall cancer (hazard ratio for higher v non-consumers or lower consumers 1.16 (95% confidence interval (CI) 1.07 to 1.26); absolute risk of cancer at age 60 years, respectively, 13.3%, 12.1%) and breast cancer (1.22 (1.05 to 1.41); 5.7%, 4.8%); total sorbates, specifically potassium sorbate, with overall cancer (1.14 (1.04 to 1.24); 13.4%, 11.8%) and breast cancer (1.26 (1.07 to 1.49); 5.7%, 4.6%); total sulfites with overall cancer (1.12 (1.02 to 1.24); 13.4%, 11.9%); potassium metabisulfite with overall cancer (1.11 (1.03 to 1.20); 13.5%, 12.0%) and breast cancer (1.20 (1.04 to 1.38); 5.7%, 4.9%); sodium nitrite with prostate cancer (1.32 (1.02 to 1.70); 4.2%, 3.4%); potassium nitrate with overall cancer (1.13 (1.05 to 1.23); 14.0%, 12.0%) and breast cancer (1.22 (1.05 to 1.41); 5.9%, 4.8%); total acetates with overall cancer (1.15 (1.06 to 1.25); 14.3%, 12.2%) and breast cancer (1.25 (1.07 to 1.45); 6.1%, 4.9%); acetic acid with overall cancer (1.12 (1.01 to 1.25); 14.4%, 12.4%); and sodium erythorbate with overall cancer (1.12 (1.04 to 1.22); 13.5%, 11.9%) and breast cancer (1.21 (1.04 to 1.41); 5.7%, 4.8%). 11 of the 17 individually studied preservatives were not associated with cancer incidence. Conclusion Multiple positive associations between intake of preservatives widely used in industrial foods and higher cancer incidence (overall, breast, and prostate) were observed in this large prospective cohort. Epidemiology based on health effect biomarkers and experimental research are needed to gain insight into outcome pathways. If confirmed, these new data call for the re-evaluation of regulations governing the food industry’s use of these additives, to improve consumer protection. In the meantime, the findings support recommendations for consumers to favour freshly made, minimally processed foods. Trial registration ClinicalTrials.gov NCT03335644 .