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Background The outcome of severely injured or ill patients can be time dependent. Short activation and approach times for emergency medical service (EMS) units are widely recognized to be important quality indicators. The use of a helicopter emergency medical service (HEMS) can significantly shorten rescue missions especially in mountainous areas. We aimed to analyze the HEMS characteristics that influence the activation and approach times. Methods In a multi-centre retrospective study, we analyzed 6121 rescue missions from nine HEMS bases situated in mountainous regions of four European countries. Results We found large differences in mean activation and approach times among HEMS bases. The shortest mean activation time was 2.9 minutes; the longest 17.0 minutes. The shortest mean approach time was 10.4 minutes; the longest 45.0 minutes. Short times are linked (p < 0.001) to the following conditions: helicopter operator is not state owned; HEMS is integrated in EMS; all crew members are at the same location; doctors come from state or private health institutions; organization performing HEMS is privately owned; helicopters are only for HEMS; operation area is around 10.000 km2; HEMS activation is by a dispatching centre of regional government who is in charge of making decisions; there is only one intermediator in the emergency call; helicopter is equipped with hoist or fixed line; HEMS has more than one base with helicopters, and one team per base; closest neighboring base is 90 km away; HEMS is about 20 years old and has more than 650 missions per year; and modern helicopters are used. Conclusions An improvement in HEMS activation and approach times is possible. We found 17 factors associated with shorter times.