Toll-like receptors (TLRs) 2 and 4 recognize different endogenous and exogenous agonists and play a distinct role in infection and inflammation. However, their ultimate effect in a given infectious and inflammatory disease is less understood. We produced polyclonal anti-murine TLR2 and TLR4 antibodies and investigated their effect on cutaneous leishmaniasis and inflammatory arthritis. Administration of these antibodies to susceptible BALB/c mice, infected in the footpad with Leishmania major, reduced footpad swelling but not the parasite load compared with mice treated with control IgG. The antibodies synergistically reduced leishmanial-specific T-cell proliferation, T helper type 1 and type 2 cytokine production, specific IgG1 and IgG2a antibody synthesis, and T-cell receptor and co-stimulatory molecule expression on dendritic cells in infected mice. We then tested the effect of these antibodies on collagen-induced arthritis (CIA) in DBA/1 mice, a classic model of chronic inflammation. Both antibodies markedly suppressed the development of clinical parameters with concomitant reduction of pro-inflammatory cytokine production. These data therefore suggest that anti-TLR2 and 4 antibodies may have a synergistic therapeutic effect on inflammatory disease in vivo.