A comparative analysis of the intermolecular energy for a data set including 60 molecular crystals with a large variety of functional groups has been carried out using three different computational approaches: (i) a method based on a physically meaningful empirical partition of the interaction energy (PIXEL), (ii) density functional methods with a posteriori empirical correction for the dispersion interactions (DFT-D), and (iii) a full periodic ab initio quantum mechanical method based on Moller-Plesset perturbation theory for the electron correlation using localized crystal orbitals (LMP2). Due to the large computational cost, LMP2 calculations have been restricted to a subset of seven molecular crystal comprising benzene, formic acid, formamide, succinic anhydride, urea, oxalic acid, and nitroguanidine, and the results compared with PIXEL and DFT-D data as well as with the experimental data show excellent agreement among all adopted methods. This shows that both DFT-D and PIXEL approaches are robust predictive tools for studying molecular crystals. A detailed analysis shows a very similar dispersion contribution of the two methods across the 60 considered molecular crystals. The study also confirms that pure DFT shows serious deficiencies in properly handling molecular crystals in which the dispersive contribution is large. Due to the negligible requested computational resources, PIXEL is the method of choice in screening of a large number of molecular crystals, an essential step to predict crystal polymorphism or to study crystal growth processes. DFT-D can then be used to refine the ranking emerged from PIXEL calculations due to its general applicability and robustness in properly handling short-range interactions.