This pilot study explored the putative role of codependency as a mediator or moderator of the relationship between substance abuse in the family of origin (SAFO) and offspring medical problems in a counterbalanced multiple-treatment experiment with a heterogenous sample of adult males and females. Codependent attitude and behavior were moderators that attenuated the relationship between SAFO and two measures of acute offspring medical problems, but codependent behavior amplified the relationship between SAFO and chronic medical problems. Challenging replications are called for.