:  A PCR‐based search for splice variants of the VPAC2 G protein–coupled receptor for vasoactive intestinal peptide (VIP) revealed: (a) a short‐deletion variant in mouse lymphocytes termed VPAC2de367–380, that lacks 14 amino acids in the seventh transmembrane domain, and (b) a long‐deletion variant in human lymphocytes termed VPAC2de325–438(i325–334), that lacks 114 amino acids beginning with the carboxyl‐terminal end of the third cytoplasmic loop and has 10 new carboxy‐terminal amino acids. VPAC2de367–380 binds VIP normally, but shows reduced VIP‐evoked signaling and effects on immune functions, whereas VPAC2de325–438(i325–334) shows reduced binding affinity for VIP and a complex pattern of functional differences. These splice variants may modify the immunoregulatory contributions of the VIP–VPAC2 axis.