Subjects with Non-Hodgkin Lymphoma (NHL) have abnormal lymphocytes that multiply and accumulate to form tumors in the lymph nodes and other organs. Currently, there are no predictive models with high performance that can predict the risk of developing NHL. We present a computational framework that accurately predicts future (up to 16 years) NHL from a signature based on DNA methylation profiles of peripheral blood samples. We studied differences in specific DNA methylation levels from blood samples between future NHL group and the control group (470 samples) from two prospective cohorts. We developed a predictive model using advanced artificial intelligence methods for NHL diagnosis based on a set of key CpG sites. The validation tests showed that our signature 1) predicts mainly “control” in an independent population of 656 healthy subjects, 2) predicts “future case” with extremely accurate performance in tissue samples from four independent NHL cohorts (662, 29, 31 and 29 subjects), with one of the cohorts (662 subjects) corresponding to children with B-cell lymphoma, 3) predicts mostly healthy in a cohort of children with 74 children in remission, 4) works for both HIV positive subjects and HIV negative subjects, 5) yields almost perfect predictions regardless of the NHL subtype, and 6) is 84% accurate at predicting T-cell lymphoma in children, despite its derivation in B-cell lymphoma in adults.