In a previous retrospective study of HIV-infected patients we detected a relationship between xerostomia and the presence of cytomegalovirus in saliva. This prospective study compares 13 patients with HIV and a complaint of xerostomia and low salivary flow rates with a control group of 7 patients with HIV without xerostomia and normal salivary flow rates. Both groups were evaluated for the presence of cytomegalovirus in saliva, peripheral blood mononuclear cells, and labial minor salivary glands. Viral cultures, polymerase chain reaction, and histopathologic examination were used to detect cytomegalovirus. Xerostomia and low salivary flow rates were associated with the presence of CMV in saliva. The virus was detected in 10 of 13 xerostomia patients and 2 of 7 controls (p = 0.05, Fisher's exact test). Cytomegalovirus was detected in the saliva of patients who did not also have it in their blood suggesting a local source of virus replication such as the salivary glands. The minor salivary glands were not a major site of cytomegalovirus. Culture was more sensitive then polymerase chain reaction in detecting salivary cytomegalovirus as a result of the presence of inhibitors to the reaction in saliva. These results suggest a link between cytomegalovirus in saliva and salivary gland dysfunction in HIV-infected patients.