Various techniques are described for periodically performing a calibration routine to calibrate a low-power system clock within an implantable medical device (IMD) based on a high accuracy reference clock also included in the IMD. The system clock is powered continuously, and the reference clock is only powered on during the calibration routine. The techniques include determining a clock error of the system clock based on a difference between frequencies of the system clock and the reference clock over a fixed number of clock cycles, and adjusting a trim value of the system clock to compensate for the clock error. Calibrating the system clock with a delta-sigma loop, for example, reduces the clock error over time. This allows accurate adjustment of the system clock to compensate for errors due to trim resolution, circuit noise and temperature.