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Background: Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC., Methods: We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways., Results: Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 ( N = 137), Cluster 1 cases ( N = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery ( P < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation ( P < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes ( N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis ( P < 10 -4 ). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses ( P < 10 -6 )., Conclusions: DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways., Impact: This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics., (©2021 American Association for Cancer Research.)