New 238U-230Th and Sr isotope data from 40Ar/39Ar-dated mafic lavas of the composite cone, A.D. 1902 dacitic tephra, and 1922–present dacitic dome lavas from the Santa María–Santiaguito volcanic complex in northwestern Guatemala indicate that genesis of magma beneath the western end of the Central American volcanic arc requires sources much different than previously envisioned. Although U-series data from historical lavas along the Central American volcanic arc, including Guatemala, show variable but small degrees of either 230Th or 238U excess, 72–35 ka basalts and basaltic andesites from the Santa María cone have 15%–26% 238U excesses, among the largest measured in Central America. This implies that the mantle wedge beneath this sector of the arc was significantly modified by slab-derived fluids. A decrease in 87Sr/86Sr and (238U/230Th) ratios over the past 72 k.y. as basaltic andesite gave way to dacite is consistent with fractional crystallization coupled with progressive assimilation of crust that has relatively unradiogenic, mid-oceanic ridge basalt–like Sr isotope composition. Overall, our U-series data along with published 238U/230Th isotope results from Central America demonstrate that (1) slab-fluid flux can be high throughout Central America, including regions of relatively thick crust, and (2) the middle to lower crust beneath northwestern Guatemala may not be dominated by ancient metamorphic and granitic rocks.