Most of the Himalayan Cenozoic leucogranites are products of partial melting of metapelite sources. In the Malashan-Gyirong area (southern Tibet), the geochemical compositions of leucogranites define two groups with distinct whole-rock major elements, large ion lithophile elements, rare earth elements, high field strength elements, and Sr and Hf isotope ratios. Based on published experimental results that define generalized melting reactions of metapelitic sources, we infer that these leucogranites are the products of two different types of crustal anatexis: fluid-fluxed melting and fluid-absent melting of muscovite in metasedimentary sources. As compared to the leucogranites derived from fluid-absent melting, those from fluid-fluxed melting have relatively higher Ca, Sr, Ba, Zr, Hf, Th, and light rare earth element concentrations, and Zr/Hf, Eu/Eu*, and Nd/Nd*, but lower Rb, Nb, Ta, and U concentrations, Rb/Sr and 87Sr/86Sr ratios, and εHf(t). The geochemical differences can be explained by melting behaviors of major (muscovite, feldspar) and accessory minerals (zircon and monazite) during different modes of crustal anatexis. The systematic elemental and isotopic signatures of different types of crustal anatexis and, in particular, the coupling of major and trace elements that results from common influences on rock-forming and accessory mineral behaviors provide tools with which to refine our understanding of the nature of crustal anatexis.