Background. The mechanisms of immunity to Rickettsia conorii that have been elucidated in mouse models have not been evaluated in human tissues. Methods. In this study, quantitative real-time polymerase chain reaction was used to determine the levels of expression of inflammatory and immune mediators in skin-biopsy samples collected from 23 untreated patients with Mediterranean spotted fever (MSF). Results. In all 23 patients, the levels of intralesional expression of mRNA of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma ,interleukin (IL)-10, RANTES, and indoleamine-2,3-dioxygenase (IDO), an enzyme involved in limiting rickettsial growth by tryptophan degradation, were higher than those in control subjects; 6 of the 23 patients had high levels of inducible nitric oxide synthase (iNOS), a source of microbicidal nitric oxide. Positive correlations between TNF-alpha, IFN-gamma, iNOS, IDO, and mild/moderate MSF suggest that type 1 polarization plays a protective role. Significantly higher levels of intralesional expression of IL-10 mRNA were inversely correlated with levels of intralesional expression of IFN-gamma mRNA and TNF-alpha mRNA. The mRNA-expression level of the chemokine RANTES was significantly higher in patients with severe MSF. Conclusion. Mild/moderate MSF is associated with a strong and balanced intralesional proinflammatory and anti-inflammatory response, with a dominant type 1 immunity, whereas severe MSF is associated with increased expression of chemokine mRNA. Whether these factors are simply correlates of mild and severe MSF or contribute to antirickettsial immunity and pathogenesis remains to be determined.