The exploitation of fossil fuels in the Mediterranean Sea will likely lead to an increase in the number of offshore platforms, a recognized threat for marine biodiversity. To date, in this basin, few attempts have been made to assess the impact of offshore gas and oil platforms on the biodiversity of benthic assemblages. Here, we adopted a structured experimental design coupled with high taxonomic resolution to outline putative effects of gas platforms on soft-bottom macrofauna assemblages in the North Ionian Sea. The analysis was based on a total of 20,295 specimens of 405 taxa, almost entirely identified at species level. Multivariate and univariate analyses showed idiosyncratic patterns of assemblage change with increasing distance from the platforms. Potential reasons underlying such inconsistency are analyzed and the view that structured experimental monitoring is a crucial tool to quantify the extent and magnitude of potential threats and to provide sound baseline information on biodiversity patterns is supported.