Objective: The current study investigated the role of affect in the daily sleep quality-pain severity relationship in youth with sickle cell disease (SCD). Previous investigations have not allowed researchers to examine whether positive and negative affect work differentially in their relations with pediatric SCD pain, sleep, and the sleep-pain relationship. The current study focused on examining the possible mediating and moderating roles positive and negative affect have in the sleep-pain relationship for youth with SCD. Method: Eighty-eight youth with SCD (aged 8-17 years), and their guardians were recruited from three regional pediatric SCD clinics. Youth completed a twice daily ecological momentary assessment, where they reported on their daily pain severity, sleep quality, positive affect and negative affect. Multilevel models were calculated to examine the relationship between negative affect, positive affect, and the sleep-pain relationship. Results: Multilevel mediation analyses indicated that low positive affect mediated the daily cyclic relationships between poor sleep and high pain. Moderation analyses indicated that high negative affect strengthened the relationship between high pain severity and poor sleep quality that night. Conclusion: Further research is needed to examine the differential roles of positive and negative affect in other pain and adult SCD populations. Research examining the mechanisms by which positive and negative affect may influence the sleep-pain relationship is needed to inform future interventions to improve sleep and pain in the pediatric SCD population.