We investigated the clinical, immunologic, and imaging features of parotid enlargement in 10 children seropositive for human immunodeficiency virus (HIV) who were infected prenatally. In seven patients, sonography revealed many small hypoechoic areas suggestive of lymphoid infiltration. In three older children, large anechoic areas suggesting lymphoepithelial cysts were present. The lesions probably represent generalized lymphoid infiltration akin to pulmonary lymphoid hyperplasia, although only two of our patients had radiologic evidence of pulmonary lymphoid hyperplasia. Four of five of the children with parotid enlargement who had immunologic studies were phenotypically HLA-DR5, an immunophenotype associated with improved immune response, occurring in less than one in four in the normal population. This suggests that painless parotid enlargement may be a good prognostic sign in HIV-seropositive children. Parotid enlargement was found in 10 HIV-positive children from 6 months to 11 years old. All except one were infected prenatally.