© The Author 2016. Objective. RA patients with serum ACPA have a strong and specific genetic background. The objective of the study was to identify new susceptibility genes for ACPA-positive RA using a genome-wide association approach. Methods. A total of 924 ACPA-positive RA patients with joint damage in hands and/or feet, and 1524 healthy controls were genotyped in 582 591 single-nucleotide polymorphisms (SNPs) in the discovery phase. In the validation phase, the most significant SNPs in the genome-wide association study representing new candidate loci for RA were tested in an independent cohort of 863 ACPA-positive patients with joint damage and 1152 healthy controls. All individuals from the discovery and validation cohorts were Caucasian and of Southern European ancestry. Results. In the discovery phase, 60 loci not previously associated with RA risk showed evidence for association at P<5±10±4 and were tested for replication in the validation cohort. A total of 12 loci were replicated at the nominal level (P<0.05, same direction of effect as in the discovery phase). When combining the discovery and validation cohorts, an intronic SNP in the Solute Carrier family 8 gene (SLC8A3) was found to be associated with ACPA-positive RA at a genome-wide level of significance RA [odds ratio (95% CI): 1.42 (1.25, 1.6), Pcombined = 3.19±10±8]. Conclusions. SLC8A3 was identified as a new risk locus for ACPA-positive RA. This study demonstrates the advantage of analysing relevant subsets of RA patients to identify new genetic risk variants.