Background The introduction of next-generation sequencing into the diagnosis of neuromuscular disorders has resulted in an increased number of newly identified RYR1 variants. We hypothesize that there is an increased referral of patients to Malignant Hyperthermia (MH)-units without a personal/family history of adverse anesthetic events suspected for MH. This retrospective multicenter cohort study evaluates patient referral indications and outcomes for those without a history of an adverse anesthetic event. Methods Patients referred between 2010-2019 to the MH-units in Antwerp, Lund, Nijmegen and Toronto were included. Previously tested patients and relatives of previously tested patients were excluded. Data collection included demographics, referral details, muscle contracture and genetic testing results including REVEL scores. Referral indications were categorized into those with a personal/family history of adverse anesthetic event and other indications including exertional and/or recurrent rhabdomyolysis, RYR1 variant(s) detected in diagnostic testing in the neuromuscular clinic without a specific diagnosis (in a family member), diagnosed RYR1-related myopathy (in a family member), idiopathically elevated resting creatine kinase values, exertional heat stroke and other. Results A total of 520 medical records were included, with the three most frequent referral indications; personal history of an adverse anesthetic event (211/520; 40.6%), family history of an adverse anesthetic event (115/520; 22.1%), and exertional and/or recurrent rhabdomyolysis (46/520; 8.8%). The proportion of patients referred without a personal/family history of an adverse anesthetic event increased to 43.6% (133/305) between 2015-2019 compared to 28.4% (61/215) in 2010-2014 (P<0.001). Patients with a personal/family history of an adverse anesthetic event were more frequently diagnosed as MH susceptible (133/220; 60.5%) than those without (47/120; 39.2%), (P < 0.001). Due to missing data, 180 medical records were excluded. Conclusion The proportion of patients referred to MH-units without a personal/family history of an adverse anesthetic event has increased, with 39.2% (47/120) diagnosed as MH susceptible.