Human and mouse Na⁺-driven Cl-HCO₃ exchangers-NDCBEs-greatly differ in the sequence of their extreme cytosolic C termini. In human NDCBE (NDCBE-B), a 17-aa sequence replaces 66 aa at the equivalent position in mouse NDCBE (NDCBE-A). We performed 5'- and 3'-RACE on human brain cDNA, followed by PCR of full-length cDNAs to determine whether the human SLC4A8 gene was capable of producing the mouse-like Ct sequence. Our study confirmed the presence in human cDNA of mouse NDCBE-like transcripts (human NDCBE-A) and also disclosed the existence of three further novel NDCBE transcripts that we have called NDCBE-C, -D, and -D'. The novel NDBCE-C/D/D' transcripts initiate at a novel 'exon 0' positioned ~35 kb upstream of the first exon of NDCBE-A/B. NDCBE-C/D/D' protein products are predicted to be truncated by 54 aa in the cytosolic N terminus compared to NDCBE-A/B. Our data, combined with a new in silico analysis of partial transcripts reported by others, increases the known extent of the SLC4A8 gene by 49 kb, to 124 kb. A functional comparison of NDCBE-A/B/C/D expressed in Xenopus oocytes demonstrates that the N-terminal variation does not affect the basal functional expression of NDCBE, but those with the shorter C terminus have a 25-50% reduced functional expression compared to those with the longer Ct. By comparison with an artificially truncated NDCBE that contains neither 17-aa nor the 66-aa Ct cassette, we determined that the functional difference is due to an inhibitory effect of the 17-aa cassette of NDCBE-B/D.