A therapeutic neuromodulation system configured for providing therapy to a patient. The therapeutic neuromodulation system comprises a plurality of electrical terminals configured for being respectively coupled to a plurality of electrodes implanted within tissue, analog output circuitry configured for delivering therapeutic electrical energy between the plurality of electrical terminals in accordance with a set of modulation parameters that includes a defined current value, a voltage regulator configured for supplying an adjustable compliance voltage to the analog output circuitry, and control/processing circuitry configured for automatically performing a compliance voltage calibration process at a compliance voltage adjustment interval by periodically computing an adjusted compliance voltage value as a function of a compliance voltage margin. The control/processing circuitry may also be configured for automatically adjusting at least one of the compliance voltage adjustment interval and the compliance voltage margin during the compliance voltage calibration process.