Protic ionic liquids (PILs) have been evaluated as additives in protein crystallization trials. Ten ionic liquids were incorporated as additives along with the JCSG+ sparse matrix screen for the crystallization of lysozyme, glucose isomerase, and trypsin. When used as additives, the PILs were identified to influence the crystallization of these globular proteins. Crystal structures obtained for lysozyme with each of the 10 PILs under identical conditions showed no change in the crystal structure of the protein; however, in three of the ten cases fragments of the ionic liquids were observed to be incorporated within the protein.