Objectives: To compare the effects of dobutamine and dopexamine on systemic hemodynamics, lactate metabolism, renal function and the intramucosal-arterial PCO2 gap in norepinephrine-treated septic shock. Design: A prospective, interventional, randomized clinical trial. Setting: Adult medical/surgical intensive care unit in a university hospital. Patients: After volume resuscitation, 24 patients were treated with norepinephrine alone titrated to obtain a mean arterial pressure of 75 mmHg and a cardiac index greater than 3.5 l/min-1· m-2. Interventions: Patients were randomized to receive an infusion of dobutamine (n = 12) (5 μg/kg per min) or dopexamine (n = 12) (1 μg/kg per min). Measurements and main results: Baseline measurements included: hemodynamic parameters, renal parameters (diuresis, creatinine clearance and urinary sodium excretion), gastric mucosal-arterial PCO2 gap, arterial and mixed venous gases and arterial lactate and pyruvate levels. These measurements were repeated after 1 (H1), 4 (H4) and 24 (H24) h. No difference was found between dobutamine and dopexamine among H0 and H1, H4 and H24 values for hemodynamics. Dobutamine and dopexamine at low doses had no significant effect on mean arterial pressure, heart rate, cardiac index, oxygen delivery, oxygen consumption and pulmonary artery occlusion pressure. No patients developed arrhythmia or electrocardiographic signs of myocardial ischemia. After 4 and 24 h lactate concentration decreased in the dobutamine group from 2.4 ± 1 mmol/l to 1.7 ± 0.7 mmol/l and 1.5 ± 0.4 mmol/l, respectively, while it increased in the dopexamine group from 2.3 ± 1 mmol/l to 2.7 ± 1 mmol/l after 4 h and returned to baseline values after 24 h (2.2 ± 0.6). After 24 h the lactate/pyruvate ratio decreased in the dobutamine group from 15 ± 5 to 12 ± 3 (p < 0.05) while it was unchanged in the dopexamine group (from 16 ± 6 to 17 ± 4). Arterial pH increased in the dobutamine group from 7.35 ± 0.05 to 7.38 ± 0.07 (p < 0.05) while it was unchanged in the dopexamine group (from 7.34 ± 0.01 to 7.35 ± 0.10). The PCO2 gap decreased after 1 and 4 h in both the dobutamine and dopexamine groups (p < 0.05 with respect to baseline). When looking at individual responses, however, patients from both groups exhibited an increased gastric PCO2 gap. No difference was found between dobutamine and dopexamine for renal parameters. Conclusions: In norepinephrine-treated septic shock, low doses of neither dobutamine nor dopexamine caused significant effects on systemic hemodynamics and renal function and both dobutamine and dopexamine inconsistently improved the PCO2 gap. The present results support the need for individual measurement of the effects of catecholamine on the PCO2 gap.