Investigation of the prevalence, incidence, and determinants of post-traumatic stress disorders (PTSD) and other mental disorders associated with military deployment in international missions poses several methodological and procedural challenges. This paper describes the design and sampling strategies, instruments, and experimental procedures applied in a study programme aimed to examine military deployment-related mental health and disorders (prevalence and trajectories) and to identify vulnerability and risk factors (e.g. age, gender, type of mission, rank, and duration of deployment and a wide range of neurobiological, psychological, social, and behavioural factors). The study comprised two components. The first component, a cross-sectional study, included 1483 deployed and 889 non-deployed German soldiers (response rate, 93%) who served during the 2009 International Security Assistance Force (ISAF) mission. A standardized diagnostic instrument (Composite International Diagnostic Interview, CIDI) coupled with established questionnaires was administered to detect and diagnose PTSD and a broad spectrum of mental disorders and mental health problems. The second component, a prospective-longitudinal study, included 621 soldiers examined before (2011) and after return (2012) from the ISAF mission. In addition to the CIDI and questionnaires, several experimental behavioural tests and biological markers were implemented to probe for incident mental disorders, mental health problems and risk factors. Our methods are expected to provide greater precision than previous studies for estimating the risk for incident deployment-related and non-deployment-related disorders and their risk factors. We expect the findings to advance our understanding of a wide spectrum of adverse mental health outcomes beyond PTSD.