Summaryobjective Recent studies have shown that Graves’ disease (GD) is linked to and associated with alleles of the cytotoxic T lymphocyte antigen‐4 (CTLA4) locus. However, the true pathogenic polymorphism(s) at this locus remains uncertain. Moreover, the association studies of the promoter CTLA4(−318)C/T polymorphism in white GD populations have produced conflicting results. Therefore, we have analysed three CTLA4 single nucleotide polymorphisms, including promoter CTLA4(−318)C/T, exon 1 CTLA4(49)A/G and intron 1 CTLA4(1822)C/T in our GD cohort from the UK.patients and methods We studied 301 white patients with GD and 349 healthy ethnically matched local controls. Amongst GD probands, 129 had significant thyroid‐associated orbitopathy (TAO; NOSPECS class III or worse). The CTLA4(−318)C/T, CTLA4(49)A/G and CTLA4(1822)C/T polymorphisms were genotyped by using the restriction enzymes MseI, Bst71I and HaeIII, respectively.results We found no association between GD and alleles of CTLA4(−318)C/T. GD was found to be associated with the G allele of CTLA4(49)A/G[P = 5·9 × 10−6, odds ratio (OR) 1·65] and the T allele of CTLA4(1822)C/T (P = 7·7 × 10−6, OR 1·64). The frequencies of these alleles were significantly higher in GD probands with significant TAO than in those without TAO (G allele: P = 0·001, OR 1·68; T allele: P = 0·001, OR 1·70).conclusions The promoter CTLA4(−318)C/T polymorphism is not in linkage disequilibrium with the pathogenic polymorphism(s) at the CTLA4 locus. The alleles of both the exon 1 CTLA4(49)A/G and the intron 1 CTLA4(1822)C/T polymorphisms are associated with GD, which is stronger in patients with TAO.