Acylphloroglucinols are a broad class of phloroglucinol derivatives characterized by the presence of a COR group, where R is more often an alkyl chain. They are largely present in natural sources and exhibit a variety of biological activities, including antibacterial, antiviral, antifungal, antitumor, antioxidant, and antimalarial. This work reports the results of a systematic conformational study (in vacuo, chloroform, acetonitrile, and water) of a representative number (118) of actual and model acylphloroglucinol structures, considering the most common R chains and investigating conformational preferences and relative energies as well as the influence of specific structural features characterizing significant subsets of compounds. The study aimed at identifying patterns for conformational preferences and at singling out the conformational aspects more closely related to the individuality of different structures, as these are expected to be more closely linked to the differences in the biological activities of different compounds. The results highlight patterns enabling reliable predictions of the conformational preferences of acylphloroglucinol molecules. © 2012 Wiley Periodicals, Inc.