Helicobacter pylori genomes typically contain 8 or 9 genes that code for secreted and highly disulfide-bridged proteins designated Helicobacter cysteine-rich proteins (Hcp). Here we show that HcpA (hp0211) but not HcpC (hp1098) triggers the differentiation of human myeloid Thp1 monocytes into macrophages. Small amounts of HcpA cause the transition of round-shaped monocytes into cells with star-like morphologies, adherence to the culture dish surface, phagocytosis of opsonized fluorescent microspheres, and expression of the surface marker protein CD11b, all of which are indicative of a macrophage-like phenotype. We conclude that HcpA acts as a bacterial immune modulator similar to a eukaryotic cytokine.