The efficacy and safety of rivipansel, a predominately E-selectin antagonist, was studied in a phase 3, randomized, controlled trial for VOC requiring hospitalization (RESET). Three hundred forty-five subjects (204 adults and 141 children) were randomized and 320 were treated (162 with rivipansel, 158 with placebo) with an intravenous loading dose, followed by up to 14 additional 12-hourly maintenance doses of rivipansel or placebo, in addition to standard care. Rivipansel was similarly administered during subsequent VOCs in an open label extension (OLE) study. In the full analysis population, the median time to readiness for discharge (TTRFD), the primary endpoint, was not different between rivipansel and placebo (-5.7 hours, P=.79; hazard ratio=0.97), nor were differences seen in secondary endpoints of time to discharge (TTD), time to discontinuation of IV opioids (TTDIVO), and cumulative IV opioid use (CIVO). Mean soluble E-selectin decreased 61% from baseline after the loading dose in the rivipansel group, while remaining unchanged in the placebo group. In a posthoc analysis, early rivipansel treatment within 26.4 hr of VOC pain onset (earliest quartile of time from VOC onset until treatment) reduced median TTRFD by 56.3 hrs, reduced median TTD by 41.5 hrs, and reduced median TTDIVO by 50.5 hrs, compared to placebo (all P < 0.05). A similar subgroup analysis comparing OLE early-treatment to early-treatment RESET placebo showed a reduction in TTD of 23.1 hours (P=0.062) and in TTDIVO of 30.1 hours (P=0.087). Timing of rivipansel administration after pain onset may be critical to achieving accelerated resolution of acute VOC. Trial Registration: Clinicaltrials.gov, NCT02187003 (RESET), NCT02433158 (OLE).