Ionized Ca (Ca2+) is essential for maintaining physiologic functioning in the cardiovascular system (CVS). Sepsis affects the CVS by several mechanisms and is associated with decreased serum Ca2+. The pharmacodynamic response of the CVS to serum Ca2+ alteration was compared in acutely septic and nonseptic dogs at serum Ca2+ levels of 50%, 100%, 150% and 200% of normal baseline values. Serum Ca2+ alterations caused similar changes in both groups, although finite differences existed between septic and nonseptic subjects. Ca manipulation produced limited differences in the response of mean arterial pressure, cardiac output, left ventricular dP/dt(max), systemic (SVR) and pulmonary (PVR) vascular resistance between septic and nonseptic subjects. PVR and SVR demonstrated opposite responses during hypocalcemia; PVR was lower than baseline in both groups, whereas SVR was higher at the 50% level. No difference was evident for total oxygen consumption (V̇O2) or heart rate. In view of the limited differences in response and the failure to improve systemic V̇O2, serum Ca2+ supplementation does not afford any additional benefit in this experimental model of acute sepsis.