Background Nutrition-related chronic diseases such as cardiovascular diseases and cancer are of multiple origin, and may be due to genetic, biologic, behavioural and environmental factors. In order to detangle the specific role of nutritional factors, very large population sample cohort studies comprising precisely measured dietary intake and all necessary information for accurately assessing potential confounding factors are needed. Widespread use of internet is an opportunity to gradually collect huge amounts of data from a large sample of volunteers that can be automatically verified and processed. The objectives of the NutriNet-Santé study are: 1) to investigate the relationship between nutrition (nutrients, foods, dietary patterns, physical activity), mortality and health outcomes; and 2) to examine the determinants of dietary patterns and nutritional status (sociological, economic, cultural, biological, cognitive, perceptions, preferences, etc.), using a web-based approach. Methods/design Our web-based prospective cohort study is being conducted for a scheduled follow-up of 10 years. Using a dedicated web site, recruitment will be carried out for 5 years so as to register 500 000 volunteers aged ≥ 18 years among whom 60% are expected to be included (having complete baseline data) and followed-up for at least 5 years for 240 000 participants. Questionnaires administered via internet at baseline and each year thereafter will assess socio-demographic and lifestyle characteristics, anthropometry, health status, physical activity and diet. Surveillance of health events will be implemented via questionnaires on hospitalisation and use of medication, and linkage with a national database on vital statistics. Biochemical samples and clinical examination will be collected in a subsample of volunteers. Discussion Self-administered data collection using internet as a complement to collection of biological data will enable identifying nutrition-related risks and protective factors, thereby more clearly elucidating determinants of nutritional status and their interactions. These are necessary steps for further refining nutritional recommendations aimed at improving the health status of populations.