CASPASE-12 (CASP12) has an anti-inflammatory function during infection. To determine and if CASP12 could protect against inflammatory disease, we investigated the distribution of CASP12 alleles in African-Americans (AA) withrheumatoid arthritis (RA). CASP12 homozygous patients had lower baseline joint narrowing and total disease scores. However, there was no significant difference for distribution of CASP12 genotypes between AA controls and patients with RA, or any other clinical criteria for this disease. CASP12 homozygosity appears to be, at best a subtle protective factor for some aspects of RA in AA patients. This raises an intriguing issue as to how this protein would not have a more significant role in an inflammatory disease process.