The St. Francois Mountains contain at least two Mesoproterozoic caldera complexes, the Butler Hill and the Taum Sauk calderas, each with diameters greater than 20 km. Igneous zircons from intrusive and extrusive units within the calderas have a range of δ 18O(zircon) from 5.8 to 8.2‰ V-SMOW. These zircons are similar to other Proterozoic zircons from igneous rocks around the world and suggest a magma source from partial melting of older crust with variable mantle component. There is no significant difference in the magmatic oxygen isotope ratios between the Taum Sauk and Butler Hill calderas. Values of Δ 18O(quartz–zircon) = 2.1–2.4‰ indicating that most quartz from samples in the two calderas still preserves near-magmatic oxygen isotope ratios. The average δ 18O(quartz) from the two calderas is 8.6 ± 2.6‰. In contrast, felsic volcanic units within the Taum Sauk caldera exposed at Johnson Shut-Ins suggest interaction with water at low temperature resulting in δ 18O(quartz) as high as 16.7‰. Quartz phenocrysts within a single sample from Johnson Shut-Ins range from 8.7 up to 16.7‰. The isotope heterogeneity, coupled with evidence of healed microcracks in cathodoluminescence images, suggests low temperature hydrothermal alteration affected the volcanics during or shortly after eruption. After caldera collapse the hydrothermally altered rocks were partially re-melted and incorporated into the magma chamber as evidenced by the slight increase in δ 18O(zircon) of the resurgent dome intrusions. In contrast, the Butler Hill caldera preserves evidence of high temperature hydrothermally altered country rock assimilated into the Stono Mountain granitic ring intrusion based on low δ 18O quartz values and visible zoning in CL. The two calderas experienced different alteration histories suggesting the lack of any homogenizing regional fluid influx.