Pentraxins are a superfamily of fluid-phase protein acting as pattern recognition molecules (PRMs) of the immune system, which seems to have a key role both in inflammation and cancer. Pentraxin 3 (PTX3), the prototype of long pentraxins, plays a multifunctional role ranging between resistance against pathogens, opsonic activity via Fc receptor, modulation of inflammatory states, and clearance of apoptotic cells. Interestingly, PTX3 has the ability to influence the complement system (CS) modulation via its interaction with some key factors of the complement cascade. PTX3 sustains carcinogenesis, enriching tumor microenvironment (TEM) with pro-inflammatory molecules promoting neoplastic cell proliferation, tumor growth, angiogenesis, and metastasis spreading. The pleiotropic role of PTX3 in cancer pathogenesis is likely to be context dependent. Of note, PTX3 shows an uncertain role in cancer development by also acting as a tumor suppressor factor via inducing dysregulation of mitogenic pathways, alteration of proliferative signalling, and inhibition of neovascularization. This chapter aims to elucidate the ambivalent role of PTX3 in carcinogenesis.