The ionophore monensin improves feed efficiency (FE) by increasing sodium uptake in rumen bacteria, which alters rumen fermentation. Dietary cation-anion difference (DCAD) represents the balance between the dietary strong cations (Na and K) and strong anion (Cl) and increased DCAD also improves FE. This study tested the interaction of monensin and DCAD using sodium sesquicarbonate and potassium carbonate as the strong ion sources in 18 early to mid-lactation Holstein cows. Monensin, DCAD and the monensin-DCAD interaction had no effect on dry matter intake, milk production and milk composition, and FE. However, addition of dietary sodium and potassium increased rumen concentrations of those minerals and increased rumen acetate and decreased rumen propionate concentrations. The effect of sodium on rumen acetate and total VFA concentrations was more pronounced in the monensin diets suggesting an interaction between monensin and DCAD on rumen fermentation.