The development and analytical performance of a novel potentiometric combination ion/pCO2 sensor design for in vitro and in vivo measurements are reported. The design is based on incorporating an appropriate ionophore within the outer silicone gas permeable membranes of both conventional macro and new catheter-type pCO2 sensors. Simultaneous measurement of the potentials across the ion-selective/gas permeable membrane and the inner glass or polymer pH sensitive membrane provides the basis for continuous monitoring of both ionic and pCO2 levels with the same device. A macro-sized K+/pCO2 embodiment of the sensor is constructed from a commercial Severinghaus CO2 sensor and is used to demonstrate the principles and capabilities of the proposed design. A flexible, miniaturized (outer diameter = 1.2 mm) combination K+/pCO2 catheter sensor is also described. The catheter-type sensor is fabricated by inserting a tubular polymer membrane pH electrode into an outer silicone rubber tube doped with valinomycin. Continuous measurements of K+ and pCO2 during 6-h blood pump studies using both the macro and catheter-type combination sensors correlate well with those of conventional bench-top analyzers. In addition, continuous (4 h) intravascular measurements with the combination catheter sensor in dogs show good agreement with those of commercial blood analyzers (R = 0.984 and 0.962 for pCO2 and K+, respectively.