There is evidence that mature dendritic cells (DCs) present in the rheumatoid arthritis (RA) joint mediate immunopathology in RA. In this study, we indicate that early myeloid progenitors for DCs and DC growth factors existing in RA synovial fluid (SF) are also likely participants in the RA disease process. A fraction of cells lacking markers associated with mature DCs or DC precursors and enriched in CD34(negative) myeloid progenitors was isolated from RA SF. These cells proliferated extensively when cultured in vitro with cytokines that promote the growth of myeloid DCs (GM-CSF/TNF/stem cell factor/IL-4) and, to a lesser degree, when cultured with monocyte/granulocyte-restricted growth factors (M-CSF/GM-CSF). Mature DCs derived from RA SF progenitors with CD14-DC cytokines known to be prevalent in the inflamed RA joint (GM-CSF/TNF/stem cell factor/IL-13) were potent stimulators of allogeneic T cells and inflammatory-type Th1 responses and included CD14-DC subtypes. Cell-free RA SF facilitated DC maturation from myeloid progenitors, providing direct evidence that the inflamed RA joint environment instructs DC growth. Enhanced development of CD14-derived DCs was correlated with the presence of soluble TNFR (p55), raising the possibility that soluble TNFR also regulate CD14-derived DC growth in vivo. SF from patients with osteoarthritis contained neither myeloid DC progenitors nor DC growth factors. The existence of DC progenitors and myeloid DC growth factors in RA SF supports the concept that RA SF may be a reservoir for joint-associated DCs and reveals a compelling mechanism for the amplification and perpetuation of DC-driven responses in the RA joint, including inflammatory-type Th1 responses.