GABA(B) is a G protein-coupled receptor composed of two subunits, GABA(B1) and GABA(B2). GABA(B1) contains an endoplasmic reticulum-retention sequence and is trafficked to the cell surface only in association with GABA(B2). To determine whether the C-terminus of GABA(B2) regulates GABA(B) trafficking, we constructed forms of GABA(B2) with various C-terminal truncations and examined their surface expression. Truncation of GABA(B2) after residue 841 significantly reduced surface expression of both the subunit and the heterodimerized receptor. Turnover of the Delta841 construct, however, did not differ from that of full-length GABA(B2). To determine whether the C-terminus of GABA(B2) might target GABA(B) to neurites, cultured hippocampal neurons were transfected with the truncated GABA(B2) constructs. Truncation of GABA(B2) at residue 841 resulted in primarily somatic localization; furthermore, axonal trafficking of this construct was significantly more restricted than dendritic trafficking. Finally, to biochemically assess trafficking of the truncated GABA(B2) constructs, we digested transfected HEK293 cell lysates with endoglycosidase H. When GABA(B2) was truncated at residue 841, it became sensitive to digestion by this enzyme, indicating incomplete trafficking. Taken together, these data show that the region of the GABA(B2) C-terminus between residues 841 and 862 is important for regulating forward trafficking and neuronal targeting of the GABA(B) receptor.