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Sickle cell disease (SCD) is a genetic disorder and symptoms may be sensitive to environmental stressors. Although it has been hypothesized that exposure to outdoor air pollution could trigger acute SCD events, evidence is limited. We obtained SCD administrative data on hospital encounters in South Carolina from 2002 to 2019. We estimated outdoor air pollutant (particulate matter<2.5 μm (PM 2.5), ozone (O 3), and PM 2.5 elemental carbon (EC) concentrations at residential zip codes using spatio-temporal models. Using a random bi-directional, fixed-interval case-crossover study design, we investigated the relationship between air pollution exposure over 1-, 3-, 5-, 9-, and14-day periods with SCD hospital encounters. We studied 8410 patients with 144,129 hospital encounters. We did not observe associations among all patients with SCD and adults for PM 2.5 , O 3 , and EC. We observed positive associations among children for 9- and 14-day EC (OR: 1.05 (95% confidence interval (CI): 1.02, 1.08) and OR: 1.05 (95% CI: 1.02, 1.09), respectively) and 9- and 14-day O 3 (OR: 1.04 (95%CI: 1.00, 1.08)) for both. Our findings suggest that short-term (within two-weeks) levels of EC and O 3 and may be associated with SCD hospital encounters among children. Two-pollutant model results suggest that EC is more likely responsible for effects on SCD than O 3. More research is needed to confirm our findings. • Sickle cell disease (SCD) may be sensitive to environmental stressors • A case-crossover design was used on hospital encounter data • PM 2.5 , O 3 , and EC were generally not associated with SCD among adults • Two-week average EC and O 3 may be associated with SCD among children [ABSTRACT FROM AUTHOR]