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We have devised an approach to fabricate dense textured V2O5 thin films, which allows us to scrutinize the root cause of capacity fade in V2O5 cathodes of Li-ion batteries. Specifically, we performed in situ measurements of stress of V2O5 thin films during 50 electrochemical cycles. Surprisingly, electrochemical cycling appears to induce elastic and rate-independent deformation over a voltage range relevant to battery operation (4–2.8 V). However, the compressive stresses gradually increase with cycle number during the first few cycles, likely due to side reactions and/or residual Li left in the V2O5, even after delithiation (to 4 V). Further cycling leads to accumulated mechanical damage (e.g., fracture, delamination) and structural damage (e.g., amorphization), which ultimately result in severe capacity fade.