Oral fluids are convenient alternatives to blood sampling for evaluating significant metabolic components. Two forms of oral fluids, oral mucosal transudates (OMT) and saliva, were collected and compared for content of soluble products of immune activation. The data confirm that OMT and saliva represent distinct body fluids. The concentrations, outputs, and analyte/protein ratios of beta-2-microglobulin (beta2M), soluble tumor necrosis factor alpha receptor II (sTNFalphaRII), and neopterin were measured. Both the OMT and the saliva of most of the individuals in the control healthy populations had measurable levels of all three activation markers. When the immune system is activated, as in human immunodeficiency virus (HIV) infection, the levels of beta2M and sTNFalphaRII are increased in both OMT and saliva compared to those in a healthy control population. OMT levels correlated better with levels in serum than did saliva and appear to reflect systemic immune activation in HIV infection. Because acquisition of oral fluids is noninvasive and easily repeatable, measurement of beta2M and/or sTNFalphaRII content in OMT could be useful in the assessment of disease activity in patients with HIV infection or chronic inflammatory diseases.