A critical role for mast cells in arthritis pathogenesis has been demonstrated in the K/BxN serum transfer mouse model; however, the mechanisms by which synovial mast cells are activated to induce arthritis remains unknown. Previous studies have demonstrated a requirement for both IgG Fc receptors and complement components (C3 and C5) as well as the receptor for the anaphylotoxin C5a (C5aR, CD88) in K/BxN serum transfer arthritis. Knowing that human synovial mast cells express CD88 while mast cells at other anatomic sites lack CD88 expression, we hypothesized that synovial mast cells may require activation via CD88 for arthritis induction in the K/BxN model. To test this hypothesis, we engrafted wild-type (C57BL/6 [B6]) and CD88-deficient (CD88-/-) bone marrow-derived mast cells (BMMC) into mast cell-deficient W/Wv recipient mice. After allowing 10 weeks for engraftment, we challenged B6 and CD88-/-BMMC-engrafted W/Wv mice as well as control, non-engrafted W/Wv and wild-type mice with arthritogenic K/BxN serum. We find that CD88-/- BMMC-engrafted W/Wv mice clinically display resistance to arthritis induction equivalent to that seen in non-engrafted W/Wv mice, while B6 BMMC engraftment restores arthritis sensitivity to W/Wv mice. Histologic analyses confirm engraftment of mast cells in synovial and other tissues in CD88-/- BMMC-recipient W/Wv mice. These results demonstrate an in vivo requirement for CD88 expression by synovial mast cells for induction of inflammatory arthritis in the K/BxN arthritis model.