Glycogen‐free synthase I from human polymorphonuclear leukocytes is activated by its own substrate, glycogen, in a slow, time‐dependent proces (hysteretic activation). This lag in response to addition of glycogen depends on the concentration of glycogen, pH and temperature. At pH 7.4 and at a temperature of 30 °C, the half‐time of activation, t1/2, decreases from 89 min at 0.004 mg/ml glycogen to 6 min at 25 mg/ml. The activation is accelerated by increasing temperature and pH, but is not influenced by enzyme concentration, glucose 6‐phosphate, UDP, high ionic strength, EDTA, mercaptoethanol, glucose, sucrose or amylase limit dextrin. The Km for UDP‐glucose (0.024 mM) and the activity ratio were unchanged during the activation process.The activation can be described by vt=vf+ (vo−vf) e−kt where vt, vf and vo are velocities at times t, 0 and ∞ and k is a complex rate constant. Evidence from ultracentrifugation and kinetic studies is presented to substantiate the hypothesis that the underlying mechanism is a simple bimolecular process: enzyme + glycogen ⇌ enzyme‐glycogen complex, with the dissociation constant Ks= 0.003 mg/ml. The hysteretic activation may become rate‐limiting during experiments in vitro with synthase. The possibility of a physiological role in glycogen metabolism, perhaps in the form of a concerted hysteresis with H+ is discussed.