This paper examines the time course of changes in plasma electrolyte and acid-base composition in response to NaHCO3 and KHCO3 ingestion. It was hypothesized that skeletal muscle is involved in the correction of the ensuing plasma disturbance by exchanging ions, gasses, and fluids between cells and extracellular fluids. Five male subjects, with catheters in a brachial artery and antecubital vein, ingested 3.57 mmol/kg body mass NaHCO3 or KHCO3. While seated, blood samples were taken 30 min before ingestion of the solution, at 10-min intervals during the 60-min ingestion period, and periodically for 210 min after ingestion was complete. Blood was analyzed for gases, hematocrit, plasma ions, and total protein. With NaHCO3, arterial plasma Na+ concentration ([Na+]) increased from 143 ± 1 to 147 ± 1 (SE) meq/l, H+ concentration ([H+]) decreased by 6 ± 1 neq/l, and [Formula: see text] increased by 5 ± 1 mmHg. There was no detectable net Na+ uptake by tissues. An increased plasma strong ion difference ([SID]) accounted fully for the decrease in plasma [H+]. With KHCO3, K+ concentration increased from 4.25 ± 0.10 to 7.17 ± 0.13 meq/l, plasma volume decreased by 15.5 ± 2.3%, [H+] decreased by 4 ± 1 neq/l, and there was no change in[Formula: see text]. The decrease in [H+] in the KHCO3 trial primarily arose in response to the increased [SID]. Net K+ uptake by tissues accounted for 37 ± 5% of the ingested K+. In conclusion, ingestion of NaHCO3and KHCO3 produced markedly different fluid and ionic disturbances and associated regulatory responses by skeletal muscle. Accordingly, the physicochemical origins of the acid-base disturbances also differed between treatments. The tissues did not play a role in regulating plasma [Na+] after ingestion of NaHCO3. In contrast, the net influx of K+ to tissues played an important role in removing K+ from the extracellular compartment after ingestion of KHCO3.