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Our previous findings suggested a deleterious role for IFN-beta in human leishmaniasis, in contrast to murine leishmaniasis. In addition, an antagonistic effect of IFN-beta upon IFN-gamma bactericidal activity has been recently shown in human leprosy, another cutaneous pathology caused by an intracellular pathogen. Here we show a similar IFN-beta/gamma antagonism for both leishmanicidal activity and monocyte/macrophage CD64 expression, suggesting that high/low CD64 expression, reflecting IFN-gamma vs. IFN-beta activity, respectively, would be associated to a positive vs negative clinical outcome in human leishmaniasis. We found that ex vivo monocyte CD64 level was significantly elevated, but, unexpectedly, positively correlated to therapeutic failure in two independent cutaneous leishmaniasis cohorts (p <0.001). In a prospective study with 110 patients, systemic IFN-gamma levels at diagnosis also significantly correlated to therapeutic failure (p =0.003). To further explore a possible IFN-gamma/beta gene signature and its relationship to parasite burden in vivo, we employed nCounter technology to quantify >700 human and Leishmania RNAs in situ in biopsies from the whole clinical spectrum of human cutaneous leishmaniasis. IFN-gamma mRNA level (G6PD-normalized) was significantly and positively correlated to macrophage IFN-regulated CD64, CD80 and HLA-DR mRNAs. In contrast, IFN-beta mRNA was undetectable/low in most biopsies. Neither IFN-gamma nor IFN-beta mRNA levels were significantly correlated to parasite burden, suggesting the deleterious role of increased IFN-gamma/CD64 might be related to an exaggerated pro-inflammatory response in situ. Next, we found that CD64-targeted immunotoxins selectively induce apoptosis and decrease parasite survival in Leishmania-infected human macrophages in vitro. Finally, CD64-immunotoxin treatment in vivo decreases lesion size, parasite load and inflammation in infected HuCD64-transgenic mice, but not control WT mice. In conclusion, our results reveal the therapeutic potential of CD64-immunotoxin treatment in cutaneous leishmaniasis, but also challenge the clinical relevance of Th1 boosting, as suggested in established murine models, for therapeutic and vaccination strategies in human leishmaniasis. [Copyright &y& Elsevier]