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Despite promising reports of the use of omalizumab as add-on therapy in patients with systemic mastocytosis and recurrent anaphylaxis during specific venom immunotherapy (VIT), unpredicted adverse effects may lead to therapy failure. We present the case of a patient with systemic mastocytosis and Hymenoptera venom allergy who was administered omalizumab as add-on therapy to improve VIT tolerability after repeated severe adverse reactions despite H1/H2-antihistamine prophylaxis. We describe an unexpected discontinuation of omalizumab following successful initiation of VIT in a patient with systemic mastocytosis, with subsequent lack of tolerability of VIT. An interesting aspect of this case is the correlation of basophil activation test results with both clinical tolerability and VIT intolerance.