The accuracy of high resolution electrocardiographic (HRECG) methods for stratifying the risk of malignant ventricular arrhythmia depends on the fidelity of QRS fiducial points detection. This study aims at examining the effect of acquisition and processing variables in HRECG on the variability of QRS complex offset (QRS offset) detection in simulated and biological signals, as well as investigating the factors related to the so called uncertainty principle applied to HRECG. Successive QRS offset locations were calculated in different signals configurations including HRECG data from patients with and without ventricular late potentials and simulated data using linear and exponential functions. The expected error in QRS offset detection was assessed as a function of: i) signal characteristics (Simulated or Biological); ii) Sampling Frequency (SF); iii) Residual Noise Level (RNL); iv) QRS maximum amplitudes. The uncertainty principle was related to HRECG and a given exponential signals, and increasing RNL up to 0.5 μV. SF and RNL are outstanding factors influencing QRS offset variability. Thus, HRECG related uncertainty principle is a deterministic phenomenon associated with both HRECG signal and mathematical formulation of the terminal decay of the QRS complex to the fusion with the ST segment.