We have previously demonstrated that plasmin, but not the zymogen plasminogen, is a selective chemoattractant for human peripheral monocytes (PM) (Blood, in press). Taking into account the high sequence homology between plasmin and Lp(a), we have now investigated the chemotactic activity of Lp(a) on Percoll-isolated PM using the Costar Transwell system (pore size 5 μm). Lp(a), which was shown to be free from other PM chemoattractants such as MCP-1, MIP-1α or C5a elicited a concentration-dependent migration of PM, but not of PMN. The maximum chemotactic activity of Lp(a) was equipotent to that of the standard chemoattractant FMLP. The chemotactic effects of Lp(a) and FMLP were additive. By checkerboard analysis, Lp(a)-mediated PM locomotion was shown to be a true chemotaxis. Similar to Lp(a), recombinant apo(a) of the 18 Kringle type triggered a concentration-dependent PM migration comparable to that induced by FMLP. LDL prepared the same way as Lp(a) did not elicit significant PM chemotaxis nor did it interfere with that triggered by Lp(a). 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 via a pertussis toxin-sensitive GTP-binding protein and activation of protein kinase C as demonstrated by the effects of 1-O-hexadecyl-2-O-methyl-rac-glycerol and chelerythrine. Lp(a) triggered generation of cGMP apparently crucial for the Lp(a)-mediated chemotaxis, since an inhibitor of soluble guanylyl cyclase, LY83583, reduced both the Lp(a)-induced cGMP production as well as PM migration. The inhibitory effect of LY83583 on PM migration could be antagonized by the stable cGMP analog 8-pCPT-cGMP. Our data indicate that Lp(a) triggers PM chemotaxis via a cGMP-dependent mechanism. These findings may have important implications for the atherogenesis associated with elevated levels of Lp(a).