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The Eocene was marked by significant cooling during which the global climate was transformed from greenhouse to icehouse conditions. Notable coeval events were the India-Asia collision and the retreat of the Paratethys Sea in Asia. The Eocene section of the long and continuous sedimentary succession of the Xining Basin in Northwest China is characterized by red mudstones with intercalated gypsum and muddy-gypsiferous layers. In this study, we conducted a semi-quantitative analysis of the mineralogy of bulk samples and the clay fraction using X-ray diffraction, with the aim of characterizing the Eocene climatic evolution of the northeastern margin of the Tibetan Plateau and inland Asia. We used a new pretreatment method to address the problem of extracting sufficient clay particles from the gypsum and gypsiferous layers. The bulk mineralogy is dominated by quartz, feldspar, calcite, gypsum and dolomite; and the clay mineralogy is dominated by illite, chlorite, and smectite (including irregular mixed-layer illite-smectite (I/S)). The variations of the clay mineral assemblages indicate the occurrence of alternations between warm humid conditions and hot dry conditions, with relatively high humidity during similar to 52-50, similar to 41.5-39 and similar to 35-34 Ma. Comparison of the results with the timing of Tibetan Plateau uplift, transgressions and regressions of the Paratethys Sea, and the marine oxygen isotope record suggest that the Eocene climatic evolution of the study region was driven fundamentally by global climate change.