Erythema toxicum is a benign rash that usually presents in the first days of life and self resolves by 7 days. The rash varies in appearance from blotchy, erythematous macules to yellow pustules on an erythematous base. The lesions are most commonly located on the trunk and extremities but can be seen on the face. The lesions also may wax and wane and may change location within a few hours. If the diagnosis is in question, a pustule can be opened, and the cells treated with a Wright stain will reveal an eosinophilic predominance.

Unlike the benign nature of erythema toxicum, herpes simplex virus (HSV) causes a rash that is a warning sign to the examiner of serious infection. Infants usually acquire HSV when they pass through the birth canal and come into contact with the virus. Of note, HSV may be shed even if the mother is asymptomatic, so a negative history of maternal HSV does not rule out HSV infection in the newborn. Neonates may also become infected during pregnancy or postnatally when they come in contact with someone with herpes gingivostomatitis.

There are three classifications of neonatal infection: disease confined to the skin, eye, and mouth; confined to the central nervous system (CNS), such as encephalitis/meningitis; and disseminated disease which involves hepatitis, multiorgan failure, shock, and disseminated intravascular coagulation (DIC). CNS disease has an associated mortality of 50% and disseminated disease of at least 85% in the absence of appropriate antiviral therapy. Nearly 40% of patients with CNS or disseminated disease have skin lesions.