AbstractTo understand the origin of disease comorbidity and to identify the essential proteins and pathways underlying comorbid diseases, we developed LeMeDISCO (Large-Scale Molecular Interpretation of Disease Comorbidity), an algorithm that predicts disease comorbidities from shared mode of action proteins predicted by the artificial intelligence-based MEDICASCY algorithm. LeMeDISCO was applied to predict the occurrence of comorbid diseases for 3608 distinct diseases. Benchmarking shows that LeMeDISCO has much better comorbidity recall than the two molecular methods XD-score (44.5% vs. 6.4%) and the S_AB score (68.6% vs. 8.0%). Its performance is somewhat comparable to the phenotype method-based Symptom Similarity Score, 63.7% vs. 100%, but LeMeDISCO works for far more cases and its large comorbidity recall is attributed to shared proteins that can help provide an understanding of the molecular mechanism(s) underlying disease comorbidity. The LeMeDISCO web server is available for academic users at: http://sites.gatech.edu/cssb/LeMeDISCO.