The association of cysteinyl leukotrienes with plasma exudation allowed the authors to form the hypothesis that rates of leukotriene excretion would be increased in the acute phase of systemic capillary leak syndrome (SCLS) and that leukotriene-modifier therapy would reduce the frequency and severity of life-threatening episodes. The authors report the association of SCLS in 3 cases, 1 with seafood-induced anaphylaxis. Rates of urinary leukotriene excretion were greater during the evolution of an episode than after resolution. In a third case, the rate of urinary leukotriene excretion was significantly higher when symptoms were evolving than when they were absent (230 ± 17 vs 110 ± 6 pg/mg, P < 0.001). Treatment with a leukotriene receptor (cys-LT1) antagonist eliminated episodes in 1 patient. Treatment with the 5-lipoxygenase inhibitor zileuton was completely effective in another patient and prevented life-threatening episodes in the patient with SCLS after seafood exposure. The authors' finding that allergen exposure—associated episodes of SCLS were eliminated by allergen avoidance implies that anaphylaxis can present as SCLS. The acute phase of all 3 forms of SCLS (paraprotein associated, anaphylaxis associated, and idiopathic) is associated with increased excretion of cystinyl leukotrienes, and leukotriene-modifier treatment appears to control the disease.