Introduction <p>Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) can be refractory to treatment, and a triple combination therapy (TCT) consisting of a glucocorticoid, cyclophosphamide, and a calcineurin inhibitor is widely used in induction therapy. For progressive or severe disease despite TCT, another immunosuppressive agent, such as a Janus kinase (JAK) inhibitor, may be added to the induction regimen.</p> Method <p>A retrospective cohort study across two centers in Japan was undertaken between January 2016 and December 2024 evaluating patients with MDA5-DM receiving TCT or quadruple combination therapy (QCT) determining the presence of severe infection. The latter therapy consisted of the addition of a JAK inhibitor to the TCT. A severe infection was defined as Grade 3 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.</p> Results <p>There were 24 patients were included; TCT: n = 19 and QCT: n = 5. In the former, three (3/19, 16%), two (2/19, 11%), and three (3/19, 16%) patients had a severe bacterial infection, invasive fungal infection, and a CMV infection, respectively. In the QCT group, two (2/5, 40%), two (2/5, 40%), and four (4/5: 80%) patients had a severe bacterial infection, invasive fungal infection, and a CMV infection, respectively. CMV infections were significantly more frequent in the QCT group (<i>p</i> = 0.014). Both TCT and QCT groups had five patients each with a severe infection (5/19, 26% and 5/5, 100%, respectively) (<i>p</i> = 0.006).</p> Conclusion <p>While both TCT and QCT have infection, the QCT group may be at a higher risk, hence highlighting the need for vigilance and adequate prophylaxis.</p>