The ability of patchy populations to persist in human-dominated landscapes is often assessed using focal patch approaches, in which the local occurrence or abundance of a species is related to the properties of individual patches and the surrounding landscape context. However, useful additional insights could probably be gained through broader, mosaic-level approaches, whereby whole land mosaics with contrasting patch-network and matrix characteristics are the units of investigation. In this study we addressed this issue, analysing how the southern water vole (Arvicola sapidus) responds to variables describing patch-network and matrix properties within replicated Mediterranean farmland mosaics, across a gradient of agricultural intensification. Patch-network characteristics had a dominant effect, with the total amount of habitat positively influencing both the occurrence of water voles and the proportion of area occupied in land mosaics. The proportions of patches and area occupied by the species were positively influenced by mean patch size, and negatively so by patch isolation. Matrix effects were weak, although there was a tendency for a higher proportion of occupied patches in more intensive, irrigated agricultural landscapes, particularly during the dry season. In terms of conservation, results suggest that water voles may be able to cope well with, or even be favoured by, the on-going expansion of irrigated agriculture in Mediterranean dry-lands, provided that a number of patches of wet herbaceous vegetation are maintained within the farmland mosaic. Overall, our study suggests that the mosaic-level approach may provide a useful framework to understand the responses of patchy populations to land use change.