Objective <p>To identify pathways linking cytokine abnormalities to mortality via prognostic factors in patients with anti-melanoma differentiation-associated protein 5 antibodies (anti-MDA5 Ab).</p> Methods <p>This study included patients with anti-MDA5 Ab whose serum was available. Serum cytokine levels were measured using a multiplex bead assay. Prognostic factors were identified using Cox regression and log-rank test. Prognostic factor groups were identified using principal component analysis (PCA) and factor and cluster analyses. The association between cytokine levels and prognostic factors (groups) was examined using PCA and correlation and path analyses. A prognosis-prediction model was developed using prognostic factors from the different groups.</p> Results <p>Thirty-five patients were included in this study, of whom 31 had rapidly progressive interstitial lung disease (RP-ILD), and 14 died. We identified white blood cell (WBC), gamma-glutamyl transpeptidase (γ-GTP), lactate dehydrogenase (LDH), C-reactive protein (CRP), ferritin, and ILD-related factors (Krebs von den Lungen-6 [KL-6], surfactant protein D [SP-D], and CT score) as prognostic factors, in addition to von Willebrand factor and thrombomodulin. Two prognostic factor groups were found: Group 1 included WBC, CRP, and ILD-related factors, and Group 2 included ferritin, LDH, and γ-GTP. Both groups contributed to mortality. Group 1 was associated with IL-6, and Group 2 was related to IL-6, IL-10, and IP-10, and indirectly with TNF-α. A model using CRP (Group1) and γ-GTP (Group2) achieved an area under the curve of 0.84, which was not inferior to previously reported models.</p> Conclusions <p>Two pathways leading to poor prognosis were identified in anti-MDA5-Ab-positive patients, each marked by specific cytokine abnormalities.</p>