Background: Mediator-related symptoms in patients with systemic mastocytosis (SM) range from mild episodic to severe life-threatening events. Methods: We examined a series of 137 consecutive patients with mastocytosis (63 females and 74 males) referred to our center between 1988 and 2010. Almost all patients received prophylactic histamine receptor (HR1 and HR2) antagonists. Results: Forty-two patients suffered from one or more mediator-related symptoms (hypotension, headache, flush, abdominal cramping, diarrhea) requiring therapy (SMSY). Severe life-threatening events (grade IV) occurred in 17 patients (12%). In 4 of these 17 patients, a deteriorating clinical course was recorded. One patient died of an apallic syndrome 1.5 years after an hymenoptera sting and cerebral hypoxia. One patient was disabled for months after an insect sting and cerebral hypoxia. Two patients with smoldering SM (SSM) suffered from severe recurrent hypotension requiring hospitalization and repeated resuscitation. Symptoms in these SSM patients did not respond to any of the antimediator-type drugs applied. However, after therapy with cladribine (2CdA), a major durable response was obtained in both cases. In patients with aggressive SM and mast cell leukemia (n = 6), life-threatening mediator-related events (grade IV) were not recorded. Conclusions: SM may be accompanied by life-threatening mediator-related symptoms. Most of these patients have indolent SM or SSM. In patients with SSMSY with uncontrolled symptoms (grade IV), therapy with 2CdA should be considered.