Major and trace element, and Nd and Sr isotopic compositions of whole rocks and mineral separates from the Oligocene, alkaline Organ Needle pluton (ONP), southern New Mexico, constrain models for the differentiation of the magma body parental to this compositionally zoned and layered epizonal intrusive body. The data reveal that the pluton is rimmed by lower ε_Nd (∼ −5) and higher ⁸⁷Sr/⁸⁶Sr (∼0.7085) syenitic rocks than those in its interior (ε_Nd ∼ −2, ⁸⁷Sr/⁸⁶Sr ∼0.7060) and that the bulk compositions of the marginal rocks become more felsic with decreasing structural depth. At the deepest exposed levels of the pluton, the ε_Nd ∼ −5 lithology is a compositionally heterogeneous inequigranular syenite. Modal, compositional and isotopic data from separates of rare earth element (REE)-bearing major and accessory mineral phases (hornblende, titanite, apatite, zircon) demonstrate that this decoupling of trace and major elements in the inequigranular syenite results from accumulation of light REE (LREE)-bearing minerals that were evidently separated from silicic magmas as the latter rose along the sides of the magma chamber. Chemical and isotopic data for microgranular mafic enclaves, as well as for restite xenoliths of Precambrian granite wall rock, indicate that the isotopic distinction between the marginal and interior facies of the ONP probably reflects assimilation of the wall rock by ε_Nd ∼ −2 mafic magmas near the base of the magma system. Fractional crystallization and crystal–liquid separation of the crustally contaminated magma at the base and along the margins of the chamber generated the highly silicic magmas that ultimately pooled at the chamber top.