Depression in older adults with multiple medical comorbidities can contribute to clinical deterioration, and increased mortality. Electroconvulsive therapy (ECT) is the first-line treatment for these patients. This study aimed to evaluate the effectiveness and safety of subcutaneous (SC) ketamine as an alternative to ECT. We reviewed the medical records of all consecutive older inpatients with severe depression and multiple medical comorbidities who were referred for ECT but treated with SC ketamine over 1 year in our institution. Demographic data, DSM-5 diagnosis, MÅDRS score, and CGI score were analyzed. Twelve patients aged 67–94 years were included. All patients were rated as severely ill, 83% were women, with a mean of 12.6 (SD, 1.4) medical comorbidities. Remission was achieved in 75% of the intention-to-treat population and 100% of treatment completers. The number of sessions ranged from 1 to 6, and days until remission from 1 to 16. Patients remained without relapse for 8–28 months. SC ketamine was safe and well tolerated, and most adverse events were mild and transient. Although limited by the retrospective open-label design of the study and small sample size, our findings provide a potential new indication for ketamine: treatment of severe depression, not necessarily resistant to antidepressants, in older patients with multiple medical comorbidities, at risk of clinical deterioration, and referral for ECT. SC ketamine was highly effective in this population, with no relapse and good tolerance. Randomized controlled trials are needed to adequately test the use of ketamine in this specific group.