BACKGROUND: There is a need for additional studies on the quality of life (QOL) of elderly depressed subjects with medical comorbidity. METHOD: We conducted a 10-week, open trial of mirtazapine orally disintegrating tablets in 16 elderly subjects with major depressive disorder and one or more serious medical illnesses. Quality of life was measured by the Medical Outcomes Study Short Form-36 Health Status Survey (SF- 36). RESULTS: Treatment with mirtazapine was associated with significant reductions in clinical global impressions-severity of illness scale (CGI-S) score, the Hamilton rating scale for anxiety (HAM-A) total score, the 17-item Hamilton rating scale for depression (HAM-D) total score and the Beck depression inventory (BDI) total scores. The SF-36 "physical functioning", "role limitation physical", "vitality", "social functioning", "role limitation emotional", and "mental health" domains improved significantly. The mean mirtazapine dose at endpoint was 35 mg per day. The drug was relatively well tolerated except for three subjects who dropped out because of side effects. No drug-drug interactions or significant changes in blood pressure or heart rate occurred. CONCLUSION: Mirtazapine orally disintegrating tablets may improve depression, insomnia, anxiety, somatic symptoms, and certain quality-of-life measures in elderly depressed subjects with medical disorders. A randomized, placebo-controlled study is warranted to confirm these promising findings.