CRP, a major acute phase protein, has also been shown to bind to Leishmania lipophosphoglycan (LPG) phosphorylated disaccharide repeats in a calcium-dependent manner. Similar structures have been observed in the promastigote secretory gel (PSG) components filamentous proteophosphoglycan (fPPG) and secreted acid phosphatase (ScAP). We investigate the ability of CRP, as well as related innate immune proteins, to bind to these Leishmania phosphoglycans, to determine their potential mechanisms as virulence factors of mammalian infection. CRP binding of PSG was shown to be calcium-dependent and on the same binding cleft involved in PC-binding. PSG from a range of Leishmania species (L.aethiopica, L.panamensis, L.donovani, L.infantum, L.mexicana, L.tropica, L.amazonensis, and L.major), as well as LPG derived from different L.mexicana promastigote stages, had the ability to bind to CRP and SAP with widely varying binding capacities. ScAP was determined to be the major CRP binding component in PSG. CRP-PSG binding was shown to be a high avidity and multimeric interaction.L.mexicana LPG stage-specific variations in size and pentraxin binding characteristics, as well as calcium-dependent binding of CRP and SAP, was demonstrated. CRP, but not SAP, binding to LPG was directed at the phosphorylated disaccharide repeats. A novel, orientation-dependent interaction of SAP binding to L.mexicana LPG was observed. LPG appeared to undergo a conformational change at a threshold of CRP binding (~2.5 μg/ml), affecting subsequent CRP binding affinity. Stage-variable LPG-PSG interaction dependent on CRP and calcium was demonstrated, with interaction being significantly greater in LPG derived from infectious stage promastigotes. PSG-CRP and LPG-CRP complex, but not LPG-SAP, was shown to be capable of binding C1q. PSG-CRP complex-mediated complement generation was shown to be primarily via the classical pathway (CP), with minor alternative pathway (AP) contribution.