The psychiatric epidemiological population study NEMESIS-2 (Netherlands Mental Health Survey and Incidence Study-2) replicates and expands the first Netherlands Mental Health Survey and Incidence Study (NEMESIS-1) conducted from 1996 to 1999. The main objectives of the new study are to provide up-to-date figures on the prevalence, incidence, course and consequences of mental disorders, and to study trends in mental disorders and service use, with the use of a new sample. New topics not included in NEMESIS-1 were added, e.g. impulse-control disorders, and genetic correlates of mental disorders through gathering DNA from saliva samples. This paper gives an overview of the design of NEMESIS-2, especially of its recently completed first wave. NEMESIS-2 is a prospective study among Dutch-speaking subjects aged 18-64 years from the general Dutch population. Its baseline wave included 6646 subjects. Three waves are planned with three year-intervals between the waves. A multistage, stratified random sampling procedure was applied. The baseline wave of NEMESIS-2 was performed between November 2007 and July 2009. Face-to-face interviews were administered with the Composite International Diagnostic Interview (CIDI) 3.0. The response rate was 65.1%, and 76.4% of the respondents donated saliva. The sample was reasonably nationally representative, but younger subjects were somewhat underrepresented. In conclusion, we were able to build a comprehensive dataset of good quality, permitting several topics to be studied in the future.