The seven-transmembrane superfamily member 3 protein (TM7SF3) is a p53-regulated homeostatic factor that attenuates the development of cellular stress and unfolded protein response. Here we show that TM7SF3 localizes to nuclear speckles; eukaryotic nuclear bodies enriched in splicing factors. This rather unexpected location of a membranal protein enables it to form stable complexes with regulators of pre-mRNA splicing including DHX15, LARP7, HNRNPU and RBM14 that co-precipitate with TM7SF3. Indeed, TM7SF3 modulates alternative splicing of >400 genes, mainly splicing at the 3’end of introns. These effects are observed both in primary human pancreatic islets and in a number of cell lines, under basal conditions and under stress. Accordingly, silencing of TM7SF3 resulted in differential expression of 1465 genes (about 7% of the human genome); with 844 and 621 genes being up- or down-regulated, respectively. Our findings implicate TM7SF3, as a resident of nuclear speckles and suggest a role for seven-transmembrane proteins as regulators of alternative splicing.