Plastics are widely diffused in the oceans and their ingestion by marine organisms is raising concern for potentially adverse effects. The risk of harmful interactions with marine plastic pollution depends on the biology of the species as well as the distribution and abundance of the different plastic types. The aim of this study was to assess the occurrence of plastic ingestion by the small-spotted catshark (Scyliorhinus canicula), one of the most abundant elasmobranchs in the Mediterranean Sea. The expression levels of genes indicative of total immune system function were analyzed to gather preliminary data for further investigation of any potential correlations between plastic presence and immune activation. One hundred catsharks were collected during the Spring 2018 in two geographic locations in the southern region of the central Mediterranean Sea: 1) near Mazara del Vallo, SW Sicily and 2) near Lampedusa island, Italy's southernmost. Standard measurements were recorded for each specimen and its organs and sex was determined. The gastrointestinal tract (GIT) was preserved for plastic detection and identification. Where present, plastics (macro- and micro-) were characterized in terms of size, shape and polymer typology through microscopy and μ-Raman spectroscopy. Spleen from a subset of thirty samples was preserved for RNA extraction, then used to quantify by real time PCR the transcripts of T cell receptor beta (TCRB), T cell receptor delta (TCRD) and IgM genes. The results indicated that ingestion of plastic is widespread, with microplastics (MP, from 1 μm to <1 mm) abundantly present in nearly all samples and macroplasticplastic (MaP, > 1 cm) in approximately 18% of the specimens collected. A significant increase in the expression of TCRB, TCRD and IgM was observed in the spleen of MaP + specimens from Mazara del Vallo waters, in parallel with 67% increase in liver weight. While the presence of MP alone is not enough to induce a strong activation of the immunity, some type of plastics falling into the MaP category may be more toxic than others and crucial in the activation of the immune response. The results of this study represent a first evidence that plastic pollution represents an emerging threat to S. canicula, the Mediterranean food web and human consumers.