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Pain in sickle cell disease (SCD) is complex and heterogeneous. In this study, we examine the influence of single nucleotide polymorphisms (SNP) in the S100B gene on acute and chronic pain variation in SCD. 136 subjects with SCD recorded their baseline, non-crisis pain experience on a digital version of the McGill Pain Questionnaire, from which we obtained composite pain index (CPI) scores as a measurement for chronic pain. Utilization of emergency or urgent care owing to painful crisis was recorded as a marker for acute pain. Blood/buccal swab samples were collected and genotyped using MassARRAY iPLEX platform. Multiple linear regression analyses revealed association with higher CPI scores for rs9983698 T allele (additive: B= 4.91, p= 0.014; dominant: B= 6.43, p= 0.009), rs9722 A allele (additive: B= 4.81, p= 0.005; dominant: B= 7.80, p= 0.003), and rs11911834 T allele (additive: B= 4.75, p= 0.016; dominant: B= 6.13, p= 0.011). On the other hand, the G allele of rs1051169 associated with decreased CPI (additive: B= -6.14, p= 0.001; dominant: B= -6.56, p= 0.009; recessive: B= -9.78, p= 0.005). Further, ordinal logistic regression of utilization groups showed that the G allele of rs1051169 also associated with lower utilization (additive: B= -1.02, p= 0.0003; dominant: B= -1.20, p= 0.002; recessive: B= -1.26, p= 0.015). Employing linkage disequilibrium plot, we identified two haploblocks for these 4 SNPs. In block 1 (rs9983698-rs9722), haplotypes T-A and C-G significantly associated with CPI (B= 5.63, -4.81; p= 0.007, 0.005, respectively). In block 2 (rs1051169-rs11911834), C-T and G-G haplotypes showed significant association with CPI (B= 4.52, -6.02; p= 0.024, 0.001, respectively). S100B SNPs and haplotypes were found to associate with acute and chronic pain in SCD indicating the potential role of S100B in sickle cell pain heterogeneity. Supported by grants from the NIH (R01HL124945, R01HL098141, T32DE018381) and IDPH.