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Background Carbonic anhydrases (CA) catalyze the inter-conversion of CO2 with HCO3 and H+, and are involved in a wide variety of physiologic processes such as anion transport, pH regulation, and water balance. In mammals there are sixteen members of the classical α-type CA family, while the simple genetic model organism C. elegans codes for six αCA isoforms (cah-1 through cah-6). Methods Fluorescent reporter constructs were used to analyze gene promoter usage, splice variation, and protein localization in transgenic worms. Catalytic activity of recombinant CA proteins was assessed using Hanssons histochemistry. CA’s ability to regulate pH as a function of CO2 and HCO3 was measured using dynamic fluorescent imaging of genetically-targeted biosensors. Results Each of the six CA genes was found to be expressed in a distinct repertoire of cell types. Surprisingly, worms also expressed a catalytically-active CA splice variant, cah-4a, in which an alternative first exon targeted the protein to the nucleus. Cah-4a expression was restricted mainly to the nervous system, where it was found in nearly all neurons, and recombinant CAH-4A protein could regulate pH in the nucleus. Conclusions In addition to establishing C. elegans as a platform for studying αCA function, this is the first example of a nuclear-targeted αCA in any organism to date. General Significance A classical αCA isoform is targeted exclusively to the nucleus where its activity may impact nuclear physiologic and pathophysiologic responses.