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Cytotoxic T‐lymphocyte antigen 4 (CTLA4) polymorphisms located in the promotor region at positions −318 (C/T) and in exon 1 (49 A/G) were investigated in 138 Spanish patients (37 men and 101 women) with rheumatoid arthritis and in 305 ethnically‐matched healthy controls. When the allelic and genotypic frequencies corresponding to the CTLA4 −318 position were compared, no significant differences between patients and controls were found. However, when the CTLA4 49 A/G polymorphism was analysed, a significant increase of A/G heterozygous individuals among female patients (48.5% vs. 33.8% in controls; P=0.008; OR=2.0) was observed. This increase was absent among males (37.8%, P=NS). Analysis of the CTLA4 49 polymorphism with respect to HLA‐DRB1 typing demonstrated a significant increase of A/G heterozygosity in the HLA‐DR3‐positive patient group compared with HLA‐DR3‐negative …