A 3-week-old girl presented to the emergency room with respiratory distress and generalized maculopapular rash. The newborn was hospitalized with a presumptive diagnosis of congenital syphilis, but she died after 2 days of therapy. Tissue from the gastrointestinal tract, brain, liver, spleen, and lung was studied by using direct fluorescent antibody and immunohistochemical analysis (IHC) for Treponema pallidum. The inflammatory infiltrate was characterized by using IHC against CD3, CD20, CD68, and smooth muscle actin. The diagnosis of congenital syphilis was confirmed by demonstrating spirochetes in tissues with IHC and direct fluorescent antibody examination. IHC showed abundant treponemes in the small intestine and liver and occasional spirochetes in the meninges. Bacteria were seen as intact spirochetes, granular staining, or large extracellular collections of antigen. A constant pathologic feature throughout the tissues was concentric macrophage (CD68-positive) infiltrate around vessels, giving an onion-skin appearance. IHC identified the macrophages as the prime immune response in congenital syphilis.