In radiopharmaceutical treatments α-particles are employed to treat tumor cells. However, the mechanism that drives the biological effect induced is not well known. Being ionizing radiation, α- particles can affect biological organisms by producing damage to the DNA, either directly or indirectly. Following the principle that microdosimetry theoryaccounts for the stochastic wayin which radiation deposits energy in sub-cellular sized volumes via physical collisions, we postulate that microdosimetry represents a reasonable framework to characterize the statistical nature of direct damage induction by α-particles to DNA. We used the TOPAS-nBio Monte Carlo package to simulate direct damage produced bymonoenergetic alpha particles to different DNAstructures. In separate simulations, we obtained the frequency-mean lineal energy (yF) and dose-mean lineal energy (yD) of microdosimetric distributions sampled with spherical sites ofdifferent sizes. The total number of DNA strand breaks, double strand breaks (DSBs) and complex strand breaks per track were quantified and presented as a function of either yF or yD. The probability ofinteraction between a track and the DNA depends on how the base pairs are compacted. To characterize this variability on compactness, spherical sites of different size were used to match these probabilities ofinteraction, correlating the size-dependent specific energy (z) with the damage induced. The total number of DNA strand breaks per track was found to linearly correlate with yF and zF when using what we defined an effective volume as microdosimetric site, while the yield of DSB per unit dose linearly correlated with yD or zD, being larger for compacted than for unfolded DNA structures. The yield ofcomplex breaks per unit dose exhibited a quadratic behavior with respect to yD and a greater difference among DNA compactness levels. Microdosimetric quantities correlate with the direct damage imparted on DNA.