The haptoglobin gene is highly polymorphic in humans with strong evidence of functionally distinct biochemical phenotypes. In all human populations, three major haptoglobin phenotypes Hp 1-1, Hp 2-1, and Hp 2-2 are present, but additional phenotypes have been identified. Haptoglobin polymorphism has important biological and clinical significance. In this review, we examine the putative role of haptoglobin polymorphism in parasitic, bacterial, and viral infections. Despite many striking effects of haptoglobin polymorphism in infectious conditions, the effects of haptoglobin genetic variation upon infections are not always predictable due to the multifunctional character of the plasma protein (e.g., antibody-like properties, immunomodulation, iron metabolism). More studies on the interplay of haptoglobin polymorphism, vaccination, and susceptibility or resistance to common infections seem warranted.