To calculate the yield of direct DNA damage induced by low energy electrons using Monte Carlo generated microdosimetric spectra at the nanometer scale and examine the influence of various simulation inputs. The potential of classical microdosimetry to offer a viable and simpler alternative to more elaborate mechanistic approaches for practical applications is discussed. Track-structure simulations with the Geant4-DNA low-energy extension of the Geant4 Monte Carlo toolkit were used for calculating lineal energy spectra in spherical volumes with dimensions relevant to double-strand-break (DSB) induction. The microdosimetric spectra were then used to calculate the yield of simple and clustered DSB based on literature values of the threshold energy of DNA damage. The influence of the different implementations of the dielectric function of liquid water available in Geant4-DNA (Option 2 and Option 4 constructors), as well as the effect of particle tracking cutoff energy and target size are examined. Frequency- and dose-mean lineal energies in liquid-water spheres of 2, 2.3, 2.6, and 3.4 nm diameter, as well as, number of simple and clustered DSB/Gy/cell are presented for electrons over the 100 eV to 100 keV energy range. Results are presented for both the ‘default’ (Option 2) and ‘Ioannina’ (Option 4) physics models of Geant4-DNA applying several commonly used tracking cutoff energies (10, 20, 50, 100 eV). Overall, the choice of the physics model and target diameter has a moderate effect (up to ~10%–30%) on the DSB yield whereas the effect of the tracking cutoff energy may be significant (>100%). Importantly, the yield of both simple and clustered DSB was found to vary significantly (by a factor of 2 or more) with electron energy over the examined range. The yields of electron-induced simple and clustered DSB exhibit a strong energy dependence over the 100 eV–100 keV range with implications to radiation quality issues. It is shown that a classical microdosimetry approach for the calculation of DNA damage based on lineal energy spectra in nanometer-size targets predicts comparable results to computationally intensive mechanistic approaches which use detailed atomistic DNA geometries, thus, offering a relatively simple and robust alternative for some practical applications.< Réduire