BACKGROUND: Depletion of haptoglobin (Hp) and hemopexin (Hx) with increase in free hemoglobin and heme are important etiologies of vaso-occlusive complications in sickle cell disease (SCD). This study is the first to show an association between clinical improvement in SCD and repletion of Hp and Hx by therapeutic plasma exchange (TPE) using plasma replacement. STUDY DESIGN AND METHODS: Thirteen fresh-frozen plasma (FFP) units derived from consecutive whole blood donations were thawed at 37°C after 10 months of storage; Hp and Hx concentrations immediately postthaw and after 5 days of refrigerated storage were analyzed by enzyme-linked immunosorbent assay (ELISA). All SCD patients presenting to a single institution over a 2-year period with acute multiorgan failure syndrome resistant to red blood cell exchange (RCE) were treated with TPE with FFP replacement; concentrations of Hp, Hx, and heme were evaluated before and after TPE by ELISA. RESULTS: Plasma concentrations of Hp and Hx decreased approximately 20% (p ≤ 0.002) after 5 days of refrigerated storage. Significant mean fold increases after TPE of 10 for Hp (p < 0.005) and seven for Hx (p < 0.003) and a 30% mean decrease in heme concentrations (p = 0.07) were noted in association with clinical improvement (three patients), whereas minimal increases in Hp and Hx were associated with continued clinical deterioration in one patient. CONCLUSION: Fresh-frozen plasma rather than thawed plasma is optimal for Hp and Hx replacement. Patient data are consistent with Hp and Hx increases via TPE limiting clinical toxicity of worsened hemolysis associated with severe vaso-occlusive complications refractory to RCE in SCD.