Dirithromycin, a semisynthetic macrolide antibiotic, crystallizes in two anhydrous polymorphic forms, an amorphous form and at least nine stoichiometric solvate forms. Six of the known solvates are isomorphic, having nearly identical X-ray powder diffraction (XRPD) patterns. Differences are observed in the CP/MAS C-13 solid-state NMR spectra, which show resonances associated with the incorporated solvent molecules. Variable-temperature CP/MAS C-13 solid-state NMR spectra of the isomorphic solvates relate N,N-dimethylamine peak coalescence temperatures with steric hindrance of included solvent molecules. The crystal structure of the thermodynamically stable anhydrous polymorphic form, a 1-propanol solvate, and a cyclohexane trisolvate form are reported and compared to that of the previously reported acetonitrile trihydrate crystal form. The crystal packing, hydrogen-bonding networks, and molecular conformations are related to the spectroscopic properties of the various crystal forms and an amorphous form. The FTIR lactone carbonyl stretching frequency and the C-13 solid-state NMR chemical shift of the lactone carbon resonance are related to the presence or absence of hydrogen bonding to this group. This study shows the usefulness of these combined spectroscopic techniques for the study of solids with structures that have not been determined. Furthermore, the study demonstrates the wide range of crystallographic forms in which macrolide antibiotics exist.