The objective of this study was to determine the feasibility of protocol-driven human recombinant hyaluronidase (rHuPH20)-enhanced subcutaneous (SC) hydration and opioid administration in adults presenting to the emergency department (ED) with sickle cell disease acute pain episodes (SCDAPE). Adults with SCDAPE were given 150 U of rHuPH20 and normal saline subcutaneously. Opioids were administered SC every 15 minutes for 4 hours until numerical rating scale (NRS) pain intensity scores fell to <5, or Ramsay Sedation Scores were >4. Pain intensity and pain relief were recorded hourly. Total morphine equivalents and fluid volume, total pain relief (TOTPAR), patient- and physician-perceived global efficacy, patient-perceived global SC needle discomfort, physician-rated ease of needle placement, and adverse effects were noted. Ten patients (6 males, 4 females), mean age 32.9 years (23-56 years) completed the trial. Mean pain intensity scores fell 25% (from 9.2 to 6.9) from baseline and mean 4-hour TOTPAR score was 4 (maximum: 16). A mean total of 119 mg (70-170 mg) morphine equivalents and 846 mL (200-1650 mL) normal saline were administered. Mean patient and physician global perceived efficacy ratings were 3.4 and 4.2 (of 5). Patient global discomfort of SC needle presence was 2.7 (of 10), and ease of needle placement was physician rated at 4 (of 4; easiest). Patients experienced mild swelling and stinging at the SC site, and no infusion required discontinuation. The authors conclude that rHuPH20-enhanced subcutaneous hydration and opioid administration appear feasible from this pilot study. These results need confirmation in a controlled clinical trial.