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This paper presents a calibration framework for a precipitation-runoff model for flood prediction in a mesoscale Alpine basin with discharges strongly influenced by hydraulic works. The developed methodology addresses two classical hydrological calibration challenges: computational limitations to run optimization algorithms for distributed hourly models and the absence of concomitant meteorological and natural discharge time series. The presented processes-oriented, multi-signal approach is based on hydrological data from a variety of sources and for different periods, corresponding to various spatial scales. The model parameters are calibrated by sequentially minimizing differences between observed and simulated values for different hydrological signals and signatures such as: (a) the phase of precipitations, (b) the time evolution of point-scale snow heights, (c) the mean inter-annual cycle of daily discharges, and (d) timing of snowmelt-induced spring runoff. We compare the model performance to a benchmark model obtained by simply using the globally optimal parameter values from the nearest gauged and non perturbed catchment. For prediction of flow seasonality and also extreme events, the calibration methodology outperforms the benchmark. Citation Hingray, B., Schaefli, B., Mezghani, A. & Hamdi, Y. (2010) Signature-based model calibration for hydrological prediction in mesoscale Alpine catchments. Hydrol. Sci. J. 55(6), 1002-1016. [ABSTRACT FROM AUTHOR]