Corticosteroids, such as prednisone and dexamethasone, are frequently prescribed medications sometimes associated with severe systemic side effects. Currently there are limited data regarding the psychiatric side effects of these medications, although mood changes and even psychoses have been reported. This study was designed to quantify psychiatric changes during brief courses of prednisone in patients with asthma. Outpatients with asthma (N = 32) receiving bursts of prednisone (>40 mg/day) were evaluated before, during, and after corticosteroid therapy by use of the Hamilton Rating Scale for Depression, the Young Mania Scale, the Brief Psychiatric Rating Scale, and the Internal State Scale. A Structured Clinical Interview for DSM-IV disorders was also conducted to examine past psychiatric history. Highly significant increases in the Young Mania Scale and Activation subscale of the Internal State Scale (both measures of mania) were observed with no increase in depression measures during the first 3 to 7 days of prednisone therapy. Mood changes were not correlated with improvement in airway obstruction, suggesting that mood elevations may not be in response to improvement in asthma symptoms. Subjects with past or current symptoms of depression had a significant decrease in depressive symptoms during prednisone therapy compared with those without depression. Some patients with posttraumatic stress disorder reported increases in depression and memories of the traumatic event during prednisone therapy. In summary, statistically significant changes in mood were observed even during brief courses of corticosteroids at modest dosages. The symptoms were primarily manic, not depressive. Persons with depression did not become more depressed during prednisone therapy, and, in fact, some showed improvement.