Several studies have shown that major depression is accompanied by significantly increased plasma levels of positive acute-phase proteins such as haptoglobin (Hp). A significant higher frequency of the HP* 1 allele has recently been detected in patients with unipolar major depression. Pursuing the hypothesis that certain unipolar and bipolar disorders may be genetically related, this study analyzed Hp genotype and allele frequencies in bipolar patients, taking into account their family history of major affective disorders. An increase of HP* 1 allele frequency was found in the subgroup of patients with family history of exclusively unipolar disorder (70% in patients vs. 38% in controls, χ2 = 8.34, p = 0.004). The relative risk for the HP*1 carriers in this subgroup was 3.8 (χ2 = 7.29, p = 0.007). These results suggest a genetic and etiological heterogeneity in the bipolar disorde