Abstract Two anti-depressant drugs, amitriptyline and imipramine, were used for the enzyme activity tests of 15-OH-PGDH purified from brain, lung, liver and kidney of mouse. Purified mouse enzymes were assayed with various concentrations of amitriptyline and imipramine (2.5 and 5.0 mM, respectively) with or without aspirin (1.6 mM). Enzyme activity of 15-OH-PGDH purified from brain, lung, liver and kidney of mouse were 12.0, 45.4, 29.8 and 0.93 nmol/min/g of tissue, respectively. Brain enzyme incubated with amitriptyline (2.5 and 5.0 mM) and imipramine (2.5 and 5.0 mM) gave 58, 233, 8.6 and 75-fold activation, respectively. Lung enzyme incubated with amitriptyline (2.5 and 5.0 mM) and imipramine (2.5 and 5.0 mM) gave 27.3, 108, 9.2 and 38-fold activation, respectively. Liver enzyme incubated with amitriptyline (2.5 and 5.0 mM) and imipramine (2.5 and 5.0 mM) gave 2.8, 20.8, 2.1 and 6.9-fold activation, respectively,. Kidney enzyme incubated with amitriptyline (2.5 and 5.0 mM) and imipramine (2.5 and 5.0 mM) gave 233, 1, 187, 235 and 803-fold activation, respectively. Aspirin (1.6 mM) had no effect on the enzyme activation. These results show that lung contains higher 15-OH-PGDH activity/g of tissue than liver, brain and kidney, and that kidney has the least. Both amitriptyline and imipramine have activatory effect on 15-OH-PGDH from mouse, especially the kidney enzyme with more than 1000-fold activation at 5.0 mM amitriptyline. This indicates that both kidney and brain enzyme might have a profound relationship with amitriptyline and imipramine concerning activatory effects.