Xanthine and a series of its methylated derivatives were evaluated as nucleating agents for poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx), and the kinetics of isothermal and nonisothermal crystallization of neat and compounded samples were evaluated via differential scanning calorimetry. Xanthine and theobromine were effective as nucleating agents, whereas caffeine and theophylline were not. Xanthine and theobromine shortened the crystallization half-lives for isothermal crystallization and decreased the ΔE a of the combined crystallization and nucleation process from −51 to −160 kJ mol −1 . The efficacy of methylxanthine derivatives in poly(hydroxyalkanoate) (PHA) nucleation correlates to the presence or absence of a hydrogen bond-donating imide nitrogen along specific crystal surface planes that may template periodic interactions within the melt despite marginal crystalline lattice parameter matching between nucleating agent and polymer crystal. The results indicate that the nucleation of PHBHHx by these imide-containing compounds is governed by periodic hydrogen bonding motifs, which do not necessarily correspond with crystalline lattice parameters.