If bipolar disorder is genetically heterogeneous, it may be possible to discern clinically heterogeneous familial subtypes based on differential risk for psychiatric comorbidity, for example panic disorder. We evaluated 528 members of 57 families ascertained for a genetic linkage study of bipolar disorder. Families were assorted according to the panic disorder diagnosis of the bipolar proband; the rates of panic and other disorders in relatives were compared. Eighty-eight percent of the 41 subjects with panic disorder had bipolar disorder. Panic disorder was diagnosed in 18% of family members with bipolar disorder. Ten of 57 bipolar probands had panic disorder. Their bipolar first-degree relatives had a significantly higher prevalence of panic disorder, bipolar II, cyclothymia, and dysthymia, but had lower prevalence of substance abuse than the relatives of the bipolar probands without panic disorder. These findings suggest the testable hypothesis that comorbid panic disorder is a marker of genetic heterogeneity in bipolar disorder.