The case-series design is being used increasingly to explore associations between environmental risk factors and genetic markers. It is demonstrated that the odds ratio derived from a case-series study is the ratio of the relative risk for developing marker-positive disease to the relative risk for developing marker-negative disease. This parameter is an empirical manifestation of etiological heterogeneity with respect to the risk factor under study, and it can be used to construct a statistical significance test. Presence of etiological heterogeneity, as reflected in departures of this parameter from unity, could be a result of either the presence of distinct causal mechanisms for the two categories of cases, or a different strength of effect via the same mechanism. The case-series approach represents an efficient and valid approach for evaluating gene-environment associations, especially in referral centers where it is difficult to identify a valid control group.