Two recent studies reported evidence for association between genetic variation of the positional candidate gene P2RX7 on chromosome 12q24 and bipolar I disorder (BPI) Barden et al. (2006); Am J Med Genet Part B 141B:374–382; McQuillin et al. (2008); Mol Psychiatry 13:1‐7 and one study found association with unipolar major depression (Mdd‐UP) Lucae et al. (2006); Hum Mol Genet 15:2438–2445. In the present work, we aimed to replicate the SNP that showed the strongest association in the above‐mentioned studies, namely rs2230912 (P2RX7‐E13A) resulting in a change of the amino acid glutamine to arginine at position 460 (Gln460Arg), in four European bipolar I disorder samples from Germany, Poland, Romania, and Russia totaling 1,445 patients, in a German sample of recurrent Mdd‐UP patients (N = 640), and a control sample of 2,006 subjects. We found no allelic or genotypic association between rs2230912 and BPI or Mdd‐UP both in the national samples and in the combined European patient sample. Additional studies are needed to clarify the potential involvement of P2RX7 and of SNP rs2230912 in the etiology of major affective disorders. © 2009 Wiley‐Liss, Inc.