Tumor necrosis factor alpha (TNF) is a key cytokine in the defense against many intracellular pathogens, including Rickettsia conorii, the causative agent of Mediterranean spotted fever (MSF). The levels of two soluble TNF receptors (sTNFR-p55 and sTNFR-p75), the extracellular domains of the two cell surface receptors for TNF, were elevated in the acute-stage plasma samples from 20 patients with serologically confirmed MSF. The median values were 3.1 and 7.8 ng/ml for sTNFR-p55 and sTNFR-p75, respectively. sTNFR values correlated significantly with plasma TNF concentrations. Patients with severe MSF had higher values for both receptor fragments than patients with nonsevere disease. The differences were statistically significant for sTNFR-p55 (median, 5.8 versus 2.0 ng/ml; P = 0.008). Given the proportionately higher values for both TNF and sTNFR-p55 in patients with severe MSF, the sTNFR-p55/TNF ratios for the two patient subgroups did not differ (P = 0.5), while the sTNFR-p75/TNF ratios were significantly different (P = 0.01), with disproportionately lower values in patients with severe disease.