Sickle cell disease (SCD) is a severe monogenic disease associated with high morbidity and mortality and a disproportionate burden on Black communities. Few population-based studies have examined the prevalence of comorbidities among persons with SCD. We estimated the prevalence of comorbidities experienced by individuals with SCD enrolled in employer-based health insurance plans in the US over their non-elderly lifetimes (0-64 years of age) with a retrospective cohort design using Truven Health MarketScan commercial claims data from 2007-2018. ICD-9/10 codes were used to identify individuals with SCD using a previously published algorithm. For this cohort, comorbidities associated with SCD were identified across 3 age categories (<18, 18-45, 46-64 years-old), based on the CMS Chronic Comorbidities Warehouse or SCD-specific diagnosis codes, when applicable. The total number of SCD patients available for analysis in each age category was 7,502 (<18 years), 10,183 (18-45 years) and 4,459 (46-64 years). Across all ages, vaso-occlusive pain, infections (non-specific), and fever were the most common comorbidities. Vaso-occlusive pain and infection were the most prevalent conditions for persons age <18- and 18-45-year-olds, while in the 46-54-year-old age group, infection and cardiovascular including pulmonary hypertension were most prevalent. Compared to persons <18 years old, the prevalence of vaso-occlusive pain, fever, and acute chest syndrome claims declined in older populations. The comorbidity burden of SCD is significant across all age groups. SCD patients experience comorbidities of age such as chronic pain, cardio-vascular conditions including pulmonary hypertension and renal disease at far higher rates than the general population. Novel disease modifying therapies in development have the potential to significantly reduce the comorbidity burden of SCD.