We examined the role of chemokines, which recruit a variety of cells, including leukocytes and endothelial cells, in rheumatoid arthritis (RA). We determined the role of the angiogenic chemokines IL-8 and epithelial neutrophil activating peptide-78 (ENA-78) in RA using a whole synovial tissue (ST) homogenate model. RA ST homogenates produced greater levels of these chemokines than did normal ST homogenates. Angiogenic chemokines often immunolocalized in proximity to ST blood vessels. RA ST homogenates contained more angiogenic activity in vitro and angiogenic activity in vivo than did normal ST extracts. Hence, IL-8 and ENA-78 are major contributors to the RA ST angiogenic activity in vitro and in vivo. To determine the role of chemokines in the development of arthritis, we examined inflammation in rats. Anti-ENA-78 diminished peritoneal neutrophil recruitment in response to rhENA-78 or lipopolysaccaride. In adjuvant-induced arthritis (AIA), a model for RA, rats produced serum ENA-78 from day 7 post adjuvant induction, even prior to the onset of clinical AIA. Joint ENA-78 was elevated in AIA rats from the onset of clinical arthritis. Prophylactic therapy of rat AIA with anti-ENA-78 prior to clinical disease onset resulted in a reduction of arthritis and a decrease in joint IL-1β and tumor necrosis factor (TNF)-α. These results suggest a role for ENA-78 in the early stages of AIA development. Efforts aimed at eliminating these angiogenic chemokines may be of benefit in the therapy of RA.