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Abstract Cyclobutane pyrimidine dimer (CPD) is a photoproduct formed by two stacked pyrimidine bases through a cycloaddition reaction upon irradiation. Owing to its close association with skin cancer, the mechanism of CPD formation has been studied thoroughly. Among many aspects of CPD, its formation involving 5‐methylcytosine (5mC) has been of special interest because the CPD yield is known to increase with C5‐methylation of cytosine. In this work, high‐level quantum mechanics/molecular mechanics (QM/MM) calculations are used to examine a previously experimentally detected pathway for CPD formation in hetero (thymine‐cytosine and thymine‐5mC) dipyrimidines, which is facilitated through intersystem crossing in thymine and formation of a triplet biradical intermediate. A DNA duplex model system containing a core sequence TmCG or TCG is used. The stabilization of a radical center in the biradical intermediate by the methyl group of 5mC can lead to increased CPD yield in TmCG compared with its non‐methylated counterpart, TCG, thereby suggesting the existence of a new pathway of CPD formation enhanced by 5mC.