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This paper addresses the reliability of flip-chip on flex (FCOF) assemblies glued with an Ag-particle filled anisotropic conductive adhesive (ACA). As the description of FCOF failure gives still much scope for speculation, a physics of failure based approach is developed here, taking into account the changing thermo-mechanical properties of the ACA under temperature and moisture. A failure hypothesis is formulated based on the loss of contact pressure. Material analysis, material characterisation, Finite Element (FE) modeling and lifetime tests have been employed to establish correlations to support this failure hypothesis. It was found, that moisture plays the most important role for interconnect failure. The model is able to predict quantitative changes of force as function of loading parameters and correlate them qualitatively to the experimental mean time to failure. New insights are provided about the stress fields at the ACA bump. The model is discussed with respect to a direct prediction of failure versus time.