Powerline contamination of recorded signals represents a major source of noise in electrophysiology and impairs the use of recordings for research. In this article we present simple and effective method for cancelling 50 Hz (or 60 Hz) noise using a reference noise signal and average noise cycle subtraction. This method is capable of reliably removing not only the fundamental powerline frequency but also its harmonic frequencies. The efficiency of this method appears to be superior to other commonly used methods such as notch filtering or adaptive filtering. Our experience and results show that this method can be efficiently used with very low signal-to-noise ratios, while preserving original signal waveform.