The mechanism of the [2 + 2] cycloaddition photoreaction of psoralen and a DNA nucleobase, thymine, cornerstone of the furocoumarin-based PUVA (psoralen + UVA radiation) phototherapy, has been studied by the quantum-chemical multiconfigurational CASPT2 method. Triplet- and singlet-mediated mono- and diadduct formations have been determined to take place via singlet-triplet crossings and conical intersections, correlated with the initially promoted triplet or singlet states in different possible reactive orientations. Pyroneside monoadducts are suggested to be formed in the triplet manifold of the system, and to be less prone to yield diadducts because of the properties of the monoadduct lowest triplet state and the minor accessibility of its excited singlet states. Furan-side monoadducts are better produced in the singlet manifold after reaching a conical intersection with the ground state of the system. From there, the absorption of a second photon would in this case trigger the formation of the diadduct. The proposed mechanisms enable rationalizing the phototherapeutic behavior of several furocoumarins.