Contamination of ascending mantle-derived magmas by the continental crust was investigated and modeled for a suite of volcanic rocks and entrained crustal xenoliths from the Central Andes using bulk geochemical compositions for mantle-derived and crustal end-members as dictated by traditional approaches. The assumption that the crustal contaminant in these open magmatic systems is a single composition was assessed through in situ analysis of quenched anatectic melt trapped within its crustal xenolith. Our results show for the first time significant chemical and Sr-isotopic disequilibrium between melt and source over submillimeter-length scales in a natural system. Sampled glass is rhyolitic in nature, enriched in large ion lithophile elements (LILE) and depleted in heavy rare earth elements (HREE). Analysis of the melt for its ⁸⁷Sr/⁸⁶Sr composition revealed isotopic heterogeneity ranging from 0.7164 to 0.7276. The isotopic disequilibrium between melt and source is understood to reflect the melting of minerals with different Rb/Sr (and therefore ⁸⁷Sr/⁸⁶Sr) more quickly than the isotopic composition can diffusively equilibrate between melt and minerals. Our results suggest that the mechanism of crustal anatexis produces contaminating melts which are geochemically heterogeneous both spatially and temporally. Furthermore, time scales of Sr diffusion and anatectic melt segregation promote the preservation of isotopic disequilibrium at the micro (submillimeter) and macro (crustal) scale. This highlights the need for detailed microscopic investigations coupled with petrogenetic modeling in order to develop more robust characterization and quantification of contamination in open magmatic systems.