Upregulation of adhesion molecules and neutrophil infiltration of venous valve cusps may be risk factors for chronic venous insufficiency. But studies that focus on the target organ (vein) fail to consider the influence of systemic inflammation on WBC behavior in the microcirculation. This study probes the gut-liver axis as a potential source of gut-derived oxidative stress and free radical production leading to white blood cell activation in chronic venous insufficiency. Venous hemodynamics (ambulatory venous pressure, air plethysmography, duplex) and gut-derived oxidative stress markers were studied in nine patients with chronic venous insufficiency (group I) and nine age- and sex-matched control subjects with no venous disease (group II). Group I had healed venous ulcers (class 5, CEAP) but near-normal ambulatory venous pressure, to eliminate high ambulatory venous pressure as a chronic venous insufficiency risk factor. Markers of gut-derived oxidative stress included: stool analysis; intestinal permeability; hepatic detoxification challenges with caffeine, salicylate, and acetaminophen; and urine lipid peroxides. Ambulatory venous pressure did not significantly differ (group I, 42.5 +/- 5.3 mm Hg; group II, 35.5 +/- 5.5 mm Hg; p = NS). Candida overgrowth in stool distinguished group I from group II (7/9 pts vs 1/9 pts, respectively; p = 0.015). Increased intestinal permeability (lactulose/mannitol ratio) was prevalent in both groups (group I 0.07 +/- 0.02, group II 0.17 +/- 0.08, p = NS; normal range, 0.01-0.03). Both groups showed similar incidence of elevated urine lipid peroxides (5/9 pts vs 6/9 pts, respectively; p = NS), yet group I exhibited underfunction of both sulfation (group I 16.8 +/- 2.9%, group II 43.3 +/- 11%, p<0.03; normal acetaminophen recovery 16-36%) and glucuronidation (group I 30.4 +/- 4.1%, group II 64.1 +/- 14.4%, p<0.04; normal acetaminophen recovery 27%-56%) relative to oxidative stress, perhaps an indicator of diminished antioxidant capacity in patients with chronic venous insufficiency. Gut dysbiosis (as indicated by stool yeast) and hepatic detoxification challenge pathway exhaustion may lead to subclinical, systemic inflammation and peripheral white blood cell adhesion in chronic venous insufficiency. Further exploration of the relationship between oxidative stress and venous disease is needed.