Objectives: The extreme sib-pair approach has been shown to be a powerful strategy to identify susceptibility loci linked to quantitative traits. The body mass index is the usually assessed trait in genetic studies on human obesity. Environmental factors clearly play an important role for this trait. We hypothesized that the low weight of most sibs who were seemingly discordant to the obese index proband was influenced by other environmental and/or genetic factors life restrained earing or psychiatric disorders. Methods: A screening questionnaire was sent to parents of all consecutively admitted patients three weeks prior to referral of index probands for inpatient treatment of obesity. The first 320 families were further investigated. Twenty-seven seemingly extremely discordant sib-pairs (ED) were identified and examined in detail. Results: The low weight of most sibs who were seemingly discordant to the obese index proband was influenced by factors like restrained eating or psychiatric disorders. Only 20% of the interviewed ED could be considered as genuine ED. Conclusion: We conclude that extensive medical evaluation is necessary if the aim is to guarantee genuine ED in family studies for human obesity. Non-paternity deserves specific attention in ED studies.