Human interleukin 10 (hIL-10), a product of monocytes, T cells, and B cells, shares extensive structural and functional similarity with viral IL-10 (vIL-10), a product of Epstein-Barr virus (EBV) replication. With two ELISAs, one that recognizes both hIL-10 and vIL-10 and the other specific for vIL-10, IL-10 was measured in serum or plasma and in saliva from 50 patients with acute EBV-induced infectious mononucleosis and from 19 normal subjects. In serum or plasma, 60% of the patients had measurable hIL-10 and/or vIL-10 and 18% had measurable vIL-10. In saliva, 20% of the patients had detectable hIL-10 and/or vIL-10 and none had detectable vIL-10. In contrast, hIL-10 and/or vIL-10 was undetectable in all 19 normal serum or plasma samples (P < .001 vs. patient samples). Among normal saliva samples, 21% had detectable hIL-10 and/or vIL-10 but none had detectable vIL-10. Thus, most patients with acute EBV-induced infectious mononucleosis transiently have abnormally high levels of circulating IL-10.