BACKGROUND: Fc gamma receptors (FcgammaRs) play a crucial role in immunity by linking IgG antibody-mediated responses with cellular effector and regulatory functions. Genetic variants in these receptors have been previously identified as risk factors for several chronic inflammatory conditions. The present study aimed to investigate the presence of copy number variations (CNVs) in the FCGR3B gene and its potential association with the autoimmune disease rheumatoid arthritis (RA). METHODOLOGY/PRINCIPAL FINDINGS: CNV of the FCGR3B gene was studied using Multiplex Ligation Dependent Probe Amplification (MLPA) in 518 Dutch RA patients and 304 healthy controls. Surprisingly, three independent MLPA probes targeting the FCGR3B promoter measured different CNV frequencies, with probe 1 and 2 measuring 0 to 5 gene copies and probe 3 showing little evidence of CNV. Quantitative-PCR correlated with the copy number results from MLPA probe 2, which detected low copy number (1 copy) in 6.7 and high copy number (>/=3 copies) in 9.4 of the control population. No significant difference was observed between RA patients and the healthy controls, neither in the low copy nor the high copy number groups (p-values = 0.36 and 0.71, respectively). Sequencing of the FCGR3B promoter region revealed an insertion/deletion (indel) that explained the disparate CNV results of MLPA probe 1. Finally, a non-significant trend was found between the novel -256A>TG indel and RA (40.7 in healthy controls versus 35.9 in RA patients; P = 0.08).