Chronic inflammation is suggested to contribute to the Philadelphia-chromosome-negative myeloproliferative neoplasm (MPN) disease initiation and progression, as well as the development of premature atherosclerosis and may drive the development of other cancers in MPNs, both nonhematologic and hematologic. The MPN population has a substantial comorbidity burden, including cerebral, cardiovascular, pulmonary, abdominal, renal, metabolic, skeletal, autoimmune, and chronic inflammatory diseases. This review describes the comorbidities associated with MPNs and the potential impact of early intervention with anti-inflammatory and/or immunomodulatory agents such as JAK-inhibitors, statins, and IFN-α to inhibit cancer progression and reduce MPN-associated comorbidity impact. Early intervention may yield a subset of patients who achieve minimal residual disease, thereby likely reducing the comorbidity burden and improving the cost-effective socioeconomic profile.