Major depression is one of the most common clinical problems seen by primary-care physicians. The prevalence is 5% to 10% in primary-care outpatients and 15% in medically ill inpatients. Despite this high prevalence rate, depression is frequently not accurately diagnosed. Evidence suggests that misdiagnosis often occurs because patients with depression frequently focus preferentially on somatic complaints or amplify complaints of chronic medical illness. The tricyclic antidepressants are more effective than placebo, both in treating medically ill patients with depression and primary-care patients with major depression. Common side effects of the tricyclic antidepressants such as the anticholinergic, cardiac, and blood-pressure problems are reviewed, with emphasis on the use of specific tricyclics in medically ill populations.