The carbonic anhydrase II (CAII) metabolon hypothesis predicts that CAII binds to electrogenic Na/HCO3 co-transporters (NBCe1), enhancing their transport of HCO3-related species. Using a short current-voltage (I-V) protocol (60 ms steps from the reversal potential, Erev), the Boron Lab (BL) showed in 2006 that neither CAII injected into Xenopus oocytes expressing NBCe1 nor CAII fused to the NBCe1 C-terminus changed NBCe1 slope conductance (G), the proper measure of NBCe1 activity. Yet in 2007, using 10 s I-V steps and a holding potential (Vh) +100 mV from Erev, Becker & Deitmer (BD) concluded the opposite. We hypothesized that the BD protocol accentuated CAII-mediated dissipation of long-distance HCO3 and intracellular pH (pHi) gradients in the cytoplasm, enhancing NBCe1 activity. However, we find that G is unchanged when Vh steps are increased to as long as 30 s. Even when NBCe1 carries large currents (approaching 2.5 μA; Vh= 0 mV), CAII does not enhance recovery rates of pHi from CO2-induced acidification, the magnitude of the peak NBCe1 current (ΔI), or G. NBCe1 functional expression levels were typically 3-fold greater in BL vs. BD experiments. However, CAII does not enhance ΔI, G, or the rate of sodium influx (d[Na]i/dt) in oocytes expressing NBCe1 at BD-equivalent levels. These experiments used an N-terminally GFP-tagged NBCe1 construct, EGFP-e1 and purified recombinant human CAII. To replicate the entire BD protocol, we expressed non-EGFP-tagged NBCe1 and injected bovine CAII purified from blood, observing a small but significant CAII-mediated change in ΔI but not G (paired t-test p<0.05). However, EGFP-e1 expressing oocytes demonstrate no CAII-dependent changes in ΔI or G. Notably, both recombinant human and purified bovine sourced-CAII enhance, in a concentration-dependent manner, d[Na]i/dt in control oocytes not expressing NBCe1. The increase is 69% inhibited by 10 µM EZA and is completely and reversibly blocked by 50 µM EIPA. Repeating the BD protocol with oocytes expressing non-EGFP-tagged NBCe1 under constant 50 µM EIPA superfusion abolishes the CAII-mediated increase in ΔI. These data indicate that the catalytic activity of CAII enhances endogenous Xenopus-oocyte Na-H exchange, and not the activity of heterologously expressed NBCe1.