Three patients demonstrated twofold to threefold changes in total-body theophylline clearance during the course of a single hospitalization for an acute illness. These changes paralleled the changes in the patients' clinical status. Theophylline clearance decreased in one patient with worsening airway obstruction, whereas clearance increased in one patient with resolving pneumonia and in one patient with improving congestive heart failure. Total-body theophylline clearance may be unstable in acute, severe illness. Close monitoring of plasma theophylline concentration in such situations will allow appropriate dose adjustments to be made and is, therefore, indicated.