The cross second virial coefficient B12 for the interaction between water (H₂O) and carbon monoxide (CO) was obtained with low uncertainty at temperatures from 200 K to 2000 K employing a new intermolecular potential energy surface (PES) for the H₂O–CO system. This PES was fitted to interaction energies determined for about 58 000 H₂O–CO configurations using high-level quantum-chemical ab initio methods up to coupled cluster with single, double, and perturbative triple excitations [CCSD(T)]. The cross second virial coefficient B12 was extracted from the PES using a semiclassical approach. An accurate correlation of the calculated B12 values was used to determine the dilute gas cross isothermal Joule–Thomson coefficient, ϕ12= B12- T(d B12/ d T). The predicted values for both B12 and ϕ12 agree reasonably well with the few existing experimental data and older calculated values and should be the most accurate estimates of these quantities to date.