The objectives of this study were two-fold: to identify tear histamine content and its relationship to changes in tear histaminase activity during the early (EPR) and late phases (LPR) of the allergic reaction induced by a conjunctival provocation test (CPT) and to evaluate the effects of lodoxamide on histamine release and allergic signs and symptoms during EPR and LPR. A baseline CPT was administered to 20 allergic patients with no baseline signs or symptoms of allergy. Clinical signs and symptoms were evaluated after 20 minutes and 6 hours. Tear samples were taken after 5-10 minutes and after 6 hours for subsequent analyses of cytology and histamine content (ELISA). Patients were then randomly assigned to receive lodoxamide or placebo four times daily for one week in a double-masked fashion. A second CPT was done after this therapy and the same parameters were re-evaluated. During EPR, tear histamine increased significantly with respect to baseline values (p < 0.05). During LPR, tear histamine increased significantly (p < 0.05) only in histamine inactivated samples. Histaminase enzymes were also significantly less active during the EPR (5.5 +/- 0.7) than the LPR (9.9 +/- 2.3) and at baseline. Histamine levels significantly correlated with allergic signs and symptoms (p < 0.05) only during the EPR. Lodoxamide significantly reduced histamine release during EPR (p < 0.05), allergic signs and symptoms during both EPR (p < 0.001) and LPR (p < 0.005), and tear cytology counts during LPR. In conclusion, greater histaminase activity may account for the smaller amount of tear histamine generally found during LPR, while these enzymes seem to play less of a role during the surge of histamine release and activity in the EPR. Lodoxamide was shown to ideally inhibit various aspects of the allergic reaction: clinical signs and symptoms in both the early and late phases, the primarily EPR-related peak of histamine release, and the primarily LPR-related changes in tear cytology.