Gut mucosal hypoperfusion plays a major role in the pathogenesis of ongoing sepsis and multiple organ dysfunction syndrome. Traditionally, therapy included increasing systemic flow, thus secondarily augmenting blood flow to the gut. Direct manipulation of the gut mucosal microcirculation avoiding systemic effects, i.e., selective gut microcirculatory control (SGMC), has not been tested with a clinically available vasodilating drug. We hypothesized that a topically applied vasoactive drug would affect gut mucosal microcirculation without systemic effects. Twelve Sprague-Dawley rats were randomly assigned to cecal ligation and perforation (CLP), or sham (SC) laparotomy. Twenty-four hours after surgery, mucosal arterioles of a 3–4 cm exteriorized ileal segment were studied using intravital microscopy while suffused with saline followed by sodium nitroprusside (SNP, 100 ±g/mL, 3.4 mM). SNP normalized (to SC saline values, 14.5 ± .6 ±m) the CLP arteriolar diameters, from 11 ± 6 to 14.6 ± .3 ±m (p < .05), while mean arterial pressure (MAP) was stable. Flowmotion patterns were also normalized by SNP, and intercapillary areas (i.e., diffusion distance) were decreased. We conclude that SNP exerted beneficial effects on gut mucosal microcirculation without affecting MAP; therefore, SGMC may be a novel way to affect the course of sepsis.