Indoleamine 2,3-dioxygenase [indoleamine: oxygen 2,3-oxidoreductase (decyclizing)] activity in the supernatant fraction (30,000 X g, 30 min) of mouse lung homogenate increased approximately 120-fold after infection with PR8 influenza virus. Both specific and total enzyme activities started to increase linearly from the 5th day after infection, reached the highest level around the 11th day, and then gradually decreased to normal values in about 3 weeks. Other enzymes in the lung, such as certain lysosomal enzymes and monoamine oxidase, did not change significantly throughout the experiments. The time course of the increase in the enzyme activity was quite different from that of virus replication in the lung (a peak by the 3rd day and persistence until the 9th day) or that of serum antibody content (started to rise on the 9th day). Rather, it appeared to be closely related to the infiltrations of mononuclear and lymphocytic cells. When mice were exposed to a higher dose of virus and did not recuperate, the time course of the increase of the enzyme activity was essentially identical to that seen with a low concentration of virus. A maximum stimulation of the enzyme activity in the lung occurred on the 9th day after infection; the increase was approximately 100-fold. However, serum antibody content was slight and virus titer in the lung remained high.