As a member of the immunoglobulin superfamily, Down syndrome cell adhesion molecule (Dscam) could function in the innate immunity of invertebrates. Recently, it is shown that arthropod Dscams play similar functions as antibodies in the adaptive immune system. Dscam could produce thousands of isoforms by alternative splicing and specifically bind to various pathogens. In the present study, we cloned the first Dscam from mud crab Scylla paramamosain (SpDscam), with full-length cDNA 7363 bp containing an open reading frame (ORF) of 6069bp and encoding 2022 amino acids, which had typical domain architecture as other arthropods, i.e., 10 immunoglobulin domains (Ig), 6 fibronectin type 3 domains (FN III), transmembrane and cytoplasmic tail. Quantitative real-time PCR revealed that SpDscam was highly expressed in brain, skin, muscle, intestine and hepatopancreas, but weakly expressed in hemolymph, heart and gill. SpDscam had three alternative splicing regions, located at the N-terminal of Ig2 and Ig3 as well as on the whole Ig7. In these regions, 32, 41 and 14 exons were detected, together with the two exon types of transmembrane domain, indicating SpDscam could potentially encode at least 36,736 unique isoforms. SpDscam induced by Vibrio parahaemolyticus challenge had strong binding ability to V. parahaemolyticus. Further, SpDscam induced by V. parahaemolyticus possessed a clearance of V. parahaemolyticus in S. paramamosain. Collectively, the results indicated SpDscam was a hypervariable pattern-recognition receptor (PRR) by alternative splicing in innate immunity system of mud crab S. paramamosain.