To analyze the relationship of the central venous-to-arterial carbon dioxide difference (
p
(cv-a)CO
2
) and cardiac index (CI) in patients with septic shock, an observational study was conducted in intensive care unit (ICU). 66 consecutive patients with septic shock and central venous oxygen saturation (ScvO
2
) ≥ 70% were included after early fluid resuscitation. Measurements were taken at a 6 h interval (T0, T6, T12, T18, T24) during first 24 h after their admission into ICU, including heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP),
p
(cv-a)CO
2
, cardiac index(CI, L/(min•m
2
)) and ScvO
2
. Patients were divided into low
p
(cv-a)CO
2
group (n = 35) and high
p
(cv-a)CO
2
group (n = 31) according to a threshold of 6 mmHg for
p
(cv-a)CO
2
at T0. As a result, at T0, T6, T12, T18 and T24, there were respectively significant differences between low and high
p
(cv-a)CO
2
groups for CI (4.1 ± 1.4 vs 2.4 ± 0.6, 4.4 ± 0.9 vs 2.8 ± 0.7, 4.1 ± 1.3 vs 2.9 ± 0.6, 4.0 ± 1.3 vs 2.7 ± 0.8, 4.2 ± 1.4 vs 2.9 ± 0.8,
p
< 0.001 at each time point), 28-day mortality rate was 38.7%(12/31) for high
p
(cv-a)CO
2
group and 22.8% (8/35) for low
p
(cv-a)CO
2
group (
p
> 0.05), there were significant differences for
p
(cv-a)CO
2
(
p
< 0.05) between low and high
p
(cv-a)CO
2
groups, no differences for HR, MAP, CVP, ScvO
2
(
p
> 0.05). CI was inversely correlated with
p
(cv-a)CO
2
value (
r
= −0.804,
p
< 0.001), but not for ScvO
2
(
r
= 0.08,
p
> 0.05). Receiver operating characteristic curve analysis confirmed the correlation of
p
(cv-a)CO
2
with CI (AUC: 0.782;
p
< 0.001; 95% confidence interval: 0.710–0.853). The cut-off value for the best predictive value of CI ≥ 2.2 L/(min·m
2
) was
p
(cv-a)CO
2
of 5.55 mmHg or lower with a sensitivity of 85.7% and specificity of 66.8%. Hence CI measured with USCOM is inversely correlated with
p
(cv-a)CO
2
values in guiding the resuscitation of patients with septic shock.
