A pressure support device implements compensation for variations in air density of its operating environment. A pressurized flow of breathable gas is generated for delivery to the airway of a subject. One or more parameters associated with the ambient environment of the pressure support device are determined. These parameters can include one or more of an ambient barometric air pressure, an ambient air temperature, or ambient air humidity. In some embodiments, one or more assumed parameters associated with the ambient environment of the pressure support device are determined based on typical sleeping conditions of the subject. An ambient air density of the ambient environment of the pressure support device is estimated based on one or more of the parameters and/or assumed parameters. A flow rate of the pressurized flow of breathable gas is adjusted based on the estimated ambient air density of the ambient environment of the pressure support device.