Background: Children and adolescents with sickle cell disease (SCD) are at increased risk for central nervous system (CNS) sequelae. Deleterious effects on CNS functioning and cognition have been well-described in terms of global intellectual functioning and specific areas of cognitive weakness. Among school-aged youth with SCD, deficits are broadly observed across a range of abilities; however, less is known about the heterogeneity in presentations of cognitive deficits in SCD and associated implications. Aims: We aimed to determine rates of comorbid cognitive deficits across specific domains of functioning and examine disease-related correlates and functional outcomes of multiple co-occurring cognitive deficits. Methods: Participants (ages 7-16 years) with SCD completed the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) and primary caregivers completed the Conners-3 to report on learning problems. WISC-V index scores were calculated for verbal comprehension, fluid reasoning, working memory, and processing speed. To investigate the heterogeneity of cognitive deficits, index scores were dichotomized and identified as a weakness if the standard score was ≤85 (i.e., 1 SD or more below the mean). Caregivers reported patient age and sex, while a review of the electronic health record was completed to verify SCD genotype and history of silent or overt cerebral infarct. Results: Ninety-one participants enrolled and completed a cognitive assessment. The mean age of participants was 10.43 years (SD=2.93) and the majority were female (59%), diagnosed with HbSS or HbS-beta0 thalassemia (75%), and had no evidence of silent or overt cerebral infarct (73%). While most participants demonstrated either no cognitive deficits or a deficit in only one domain of functioning (63%), a notable proportion of participants (37%) exhibited cognitive deficits across multiple (i.e., ≥2) domains. Nineteen percent of participants exhibited deficits in two domains of cognitive functioning, 11% had deficits in three domains, and 7% had deficits in four domains. In contrast, 17% of participants exhibited a cognitive deficit in only one domain. The most common comorbid deficits were observed for fluid reasoning and processing speed (18%) and working memory and processing speed (18%). Comorbid deficits in both verbal comprehension and working memory were the least common (9%). The number of domains ≥1 standard deviation below the mean was positively correlated with caregiver-rated learning problems (r=.38, p<.001). In a multiple linear regression controlling for age, sex, genotype, and stroke history, the number of domains of cognitive weakness significantly predicted caregiver-rated learning problems (b=4.29, p<.001). Conclusion: A high level of heterogeneity in cognitive deficits was observed in the current sample of youth with SCD. Among those with any cognitive deficits, it was more common for participants to have multiple areas of cognitive weakness than a single area of weakness. Deficits in processing speed showed high comorbidity with deficits in other areas, specifically in fluid reasoning and working memory. Having deficits across multiple areas of functioning was associated with increased learning problems. Additional research needs to examine the etiology of comorbid cognitive deficits, implications for disease self-management, and the extent to which cognitive interventions targeting multiple domains of weakness could enhance outcomes.