We present the first report of enzymatic catalysis in an ionic liquid. The virtually nonexistent vapor pressure makes ionic liquids an exciting new alternative for enzyme‐catalyzed syntheses in environmentally friendly environments. Z‐aspartame was synthesized in a thermolysin‐catalyzed reaction of carbobenzoxy‐L−aspartate and L−phenylalanine methyl ester hydrochloride in 1‐butyl‐3‐methylimidazolium hexafluorophosphate (BP6). Ionic liquids such as BP6 are thermally stable and have a remarkable range of temperatures over which they remain liquid (300 °C). With an initial rate of 1.2 ± 0.1 nmol min⁻¹ mg⁻¹, we observed a competitive rate in comparison to that of enzymatic synthesis in organic solvent. Additionally, the enzyme exhibits outstanding stability, which would normally require immobilization.