Background Thiopurines and methotrexate have long been used to maintain remission in Crohn's disease (CD). In this nationwide study, we aimed to compare the effectiveness and safety of these drugs in CD. Methods We utilized data from the epi-IIRN cohort, including all patients with CD diagnosed in Israel. Outcomes were compared by propensity-score matching and included therapeutic failure, hospitalizations, surgeries, steroid-dependency and adverse events. Results Of the 19,264 patients diagnosed with CD since 2005, 3,885 (20%) ever received thiopurines as monotherapy and 553 (2.9%) received methotrexate. While the utilization of thiopurines declined from 22% in 2012-2015 to 12% in 2017-2020, the use of methotrexate remained stable. The probability of sustaining therapy at one, three, and five years was 64%, 51%, and 44% for thiopurines and 56%, 30%, and 23% for methotrexate (p Conclusion Thiopurines demonstrated higher treatment durability than methotrexate but more frequent adverse events. However, disease outcomes were similar, partly due to more frequent escalation to biologics with methotrexate.