This work aims at investigating the nicotinamide (NA)–ethyl-paraben (EP) binary system both in solution and in the solid state. In particular, the apparent EP solubility in water was studied in the presence of different NA concentrations (between 0.28 and 1.64 M). It was found that the apparent EP solubility increase (nearly twofold) observed at the highest NA concentration tested can be ascribed to a change in the polarity of the solvent mixture, rather than to a direct effect of NA on EP. The effect of fusion and re-crystallization from water or ethanol solutions on EP and NA mixtures was investigated by means of differential scanning calorimetry, elemental analysis and X-ray diffraction both on powder and single crystal. It was discovered that EP and NA form a co-crystal having a 1:1 molar composition that can be easily crystallized from ethanol. Single crystal X-ray analysis of this species revealed that the NA and EP molecules form corrugated layers within which the two components are intimately associated by a dense network of hydrogen bonds. In the presence of an excess NA in solution, the EP-NA co-crystal has lower water solubility with respect to both the single co-crystal formers and precipitates in aqueous solutions at ambient temperature. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4830–4839, 2008