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Epithermal uranium deposits of the Sierra Peña Blanca are classic examples of volcanic-hosted deposits and have been used as natural analogs for radionuclide migration in volcanic settings. We present a new genetic model that incorporates both geochemical and tectonic features of these deposits, including one of the few documented cases of a geochemical signature of biogenic reducing conditions favoring uranium mineralization in an epithermal deposit. Four tectono-magmatic faulting events affected the volcanic pile. Uranium occurrences are associated with breccia zones at the intersection of fault systems. Periodic reactivation of these structures associated with Basin and Range and Rio Grande tectonic events resulted in the mobilization of U and other elements by meteoric fluids heated by geothermal activity. Focused along breccia zones, these fluids precipitated under reducing conditions several generations of pyrite and uraninite together with kaolinite. Oxygen isotopic data indicate a low formation temperature of uraninite, 45-55°C for the uraninite from the ore body and ∼20°C for late uraninite hosted by the underlying conglomerate. There is geochemical evidence for biological activity being at the origin of these reducing conditions, as shown by low δS values (∼−24.5‰) in pyrites and the presence of low δC (∼−24‰) values in microbial patches intimately associated with uraninite. These data show that tectonic activity coupled with microbial activity can play a major role in the formation of epithermal uranium deposits in unusual near-surface environments. [ABSTRACT FROM AUTHOR]