We evaluated the impact of the dietary cation-anion difference (DCAD) on the influence of anionic salts (AS) on the metabolism of dairy cows using a study-design that included control of feed intake. Ten mature, non-lactating, non-pregnant, Holstein-Friesian-crossbreed cows received 2000 mEq of either one of the seven anionic salts tested, two combinations of the anionic salts or water as control via a rumen cannula. Salts and controls were assigned in a 10×10 Latin square design. Whole blood, serum and urine samples were taken during treatment (TP) and washout period. Samples of whole blood were tested for pH, base-excess and bicarbonate concentrations. In urine, pH and net acid-base excretion (NABE) were analysed. Calcium was measured in serum and urine. According to the different batches of hay, five groups of DCAD were created regarding cluster analysis. Changes in urine and blood parameters were statistically analysed for each DCAD group separately. The different DCAD had an impact on the amount of change in acid-base balance (ABB) and calcium metabolism and for how long these changes lasted. In the DCAD group receiving the highest amount of AS (239 mEq/kg dry matter with AS), changes of ABB were only noticeable in urine and these changes only differed from day zero in the first week of TP (P<0·05). In the other four groups changes of ABB were also visible in blood parameters, but only on a few days of TP did the deviations differ significantly (P<0·05) from day zero. Changes of ABB parameters in urine samples were more pronounced than those in blood and differed clearly from day zero (P<0·05). Parallel to the changes of ABB, calcium concentrations in these samples were significantly increased (P<0·001) in all DCAD groups. Except for the highest DCAD group, ionized calcium concentrations changed over time (P<0·020). However, the differences were very small and only differed from day zero on a few TP days. We conclude that the DCAD of a dairy cow's diet has an important impact on the effect of AS on ABB and calcium metabolism with respect to the duration and amount of change. The target regions of DCAD should be clearly below 100 mEq/kg dry matter to ensure the desired effect on ABB and calcium metabolism. Extremely negative DCAD should be avoided to minimize the risk of clinical acidosis induced by AS.