We have previously reported that the serine protease plasmin triggers chemotaxis in human peripheral monocytes, but not in polymorphonuclear leukocyte. We now show that the structurally related lipoprotein(a) (Lp[a]) as well as recombinant apolipoprotein(a) (apo[a]) trigger chemotactic responses in human monocytes equipotent to that observed with the standard chemoattractant FMLP. The chemotactic effects of Lp(a) and FMLP were additive. Low density lipoprotein (LDL) did not elicit any significant chemotactic response nor did it interfere with that triggered by Lp(a). As assessed by checkerboard analysis, Lp(a)-mediated monocyte locomotion was a true chemotaxis. Both plasminogen as well as catalytically inactivated plasmin inhibited monocyte migration elicited by Lp(a), suggesting binding of Lp(a) to plasminogen binding sites. Lp(a)-mediated signaling proceeds through a pertussis toxin-sensitive guanosine triphosphate (GTP)-binding protein and activation of protein kinase C as implicated by the effects of 1-O-hexadecyl-2-O-methyl-rac-glycerol and chelerythrine. Lp(a) induced generation of guanosine 3′,5′-cyclic monophosphate (cGMP), apparently crucial for the Lp(a)-mediated chemotaxis, because an inhibitor of soluble guanylyl cyclase, LY83583, reduced both the Lp(a)-induced cGMP formation as well as the monocyte migration. The latter effect of LY83583 was antagonized by the stable cGMP analog 8-pCPT-cGMP. The data indicate that Lp(a) triggers chemotaxis in human monocytes by way of a cGMP-dependent mechanism. Our findings may have important implications for the atherogenesis associated with elevated levels of Lp(a).