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Introduction: Fenoldopam is a selective dopamine-1 receptor agonist, which has mainly been studied as a possible prophylactic agent against contrast-induced nephropathy. Despite some promising clinical data, there is a lack of knowledge regarding fenoldopam's mechanism of action in septic shock. Methods: Sepsis was established in sheep by injecting 1.5 g/kg of autologous feces into the abdominal cavity; 2 hours later, the animals were randomized to receive either placebo or fenoldopam intravenously at a rate of 1.0 µg/kg/min for 16 hours. The two groups were assessed for differences in general hemodynamics, kidney oxygen-derived variables (oxygen delivery (K-DO2), oxygen consumption (K-VO2) and oxygen extraction ratio (K-O2ER)) and the metabolic response (L/P ratio) of both renal cortex and medulla using microdialysis (CMA20, CMA, Sweden). Results: Throughout the course of the experiment, animals treated with the vasodilator fenoldopam had a significantly lower mean arterial pressure (p < 0.05) and higher blood lactate levels (p <0.05) compared to controls. After an initial increase, K-DO2 decreased in fenoldopam-treated animals when shock developed, to the same level as that of control animals. In the face of a reduction in perfusion pressure, K-O2ER doubled as K-VO2 remained constant. Metabolic stress was apparent with lactate/pyruvate ratios and lactate levels increasing early in cortex and medulla. Conclusions: In this sheep model of septic shock, fenoldopam-administration was associated with a worsening of general hemodynamic and renal metabolic parameters.