The effect of ephedrine (E) and theophylline (T), administered alone and in combination (E/T), on weight loss, resting energy expenditure and post-heparin lipoprotein lipase activity in plasma (PHLA) and in adipose tissue (ATLP) were investigated in obese over-fed rats, who had been diet restricted (-40% of normal caloric intake) for three weeks. E, T and E/T significantly increased weight loss in all experimental groups as compared to the controls. Weight loss was achieved not only by preventing the adaptive fall in resting energy expenditure associated with diet restriction, but by raising it above basal level. The effect of E/T mixture was no greater than that of E or T alone. E, T and E/T administration increased PHLA in plasma while hypocaloric diet alone did not influence the activity of the enzyme. ATLP in the epididymal fat pads decreased insignificantly in all experimental groups, as well as in the controls. Serum cholesterol levels were not influenced by hypocaloric diet and by drug administration, but serum triglycerides increased significantly in E, T and E/T treated groups. The elevation of PHLA after ephedrine and/or theophylline administration was mostly due to an increase in the hepatic lipase (HL) level. This enzyme contributes to the removal of the atherogenic intermediate density lipoproteins from blood serum. The increased HL activity in drug-treated, diet-restricted obese rats may therefore play a role in the prevention of atherosclerosis.