Host genetic factors determine the individual natural course of HIV infection and influence the response to therapy and the occurrence of adverse events to treatment. Variants of multiple genes are associated with faster but also slower development of severe immunodeficiency. However, only very rarely the variant of one single gene explains a specific clinical phenotype. But multiple genetic marker form a complex trait, which is difficult to analyse biostatistically. Research in this rapidly evolving field asks for structures in which hypotheses can be generated and evaluated and which combine basic and diagnostic and therapeutic research. The large amount of prospective information on HIV disease natural history and treatment response of the Swiss HIV Cohort Study will make of the Genetics project an excellent test-setting for some of the immediate difficulties in this research field: validation of new markers and modelling of complex traits.