Background: Recombinant human hyaluronidase (rHuPH20) (150 U) is approved by the US Food and Drug Administration to facilitate subcutaneous fluid administration in adults and children. Objective: This Phase IV, double-blind, randomized pilot study was designed to compare the tolerability, flow rate, and safety profile of subcutaneous infusions of normal saline (NS) and lactated Ringer's (LR) solutions following subcutaneous administration of rHuPH20. Methods: Healthy volunteers received 1 mL rHuPH20 (150 U) in each thigh, followed by simultaneous gravity-driven subcutaneous infusions of 500 mL of LR solution into 1 thigh and NS solution into the contralateral thigh. Subjects rated infusion-site discomfort in each thigh using a 100-mm (0 = no pain to 100 = most severe pain) visual analog scale (VAS) at baseline (ie, after catheter placement/ rHuPH20 injection and just prior to the start of the infusions) and at the following times: after infusion of 250 mL, after infusion of 500 mL (end of infusion), and when thigh circumference returned to within 5% of baseline. Adverse events (AEs) were recorded throughout the study. The primary tolerability end point was the maximal increase from baseline in infusion-site discomfort on the VAS. Secondary end points included infusion flow rate, change in thigh circumference, subject preference for leftversus right-thigh infusion, and safety profile measures. Results: Fifteen subjects (14 women, 1 man; mean age, 41 years [range, 20–60 years]) were included in the study. Mean (SD) maximal increase from baseline VAS pain score was significantly greater with NS solution than with LR solution (20.0 [19.4] vs 9.4 [18.3] mm, respectively; P = 0.005). Mean infusion flow rate was not significantly different between the NS and LR solutions (384.1 [118.1] vs 395.8 [132.8] mL/h). No significant differences between solutions were observed in mean maximal change in thigh circumference (5.2% [1.6%] vs 5.3% [1.5%]). All subjects expressed global preference for LR infusion over NS infusion. All subjects experienced ≥1 AE; the majority of AEs were mild, localized infusion-site reactions. Of all AEs (regardless of their relationship to study drug or procedure), 81% were mild injectionsite reactions that were similar in nature for the NS and LR solutions. Although the types of mild local AEs were similar for the 2 infusions, they were numerically more common with NS infusions (15 subjects [100%]) than with LR infusions (9 subjects [60%]). For the NS and LR solutions, the most frequent infusion-site AEs were pain (67% vs 40%, respectively), erythema (47% vs 13%), and irritation (27% vs 20%). Conclusions: This small pilot study found that the mean maximal increase from baseline in self-assessed pain VAS scores was statistically significantly higher with NS solution than LR solution. In addition, all subjects preferred LR solution to NS solution, and the incidence of some infusion-site AEs was numerically greater with NS solution. Although the VAS score indicated a statistically significant difference in tolerability favoring LR, the modest changes from baseline suggest both solutions were generally well tolerated and support the use of both NS and LR, as appropriate, for rHuPH20-facilitated subcutaneous isotonic fluid infusion in healthy adults. These results need to be confirmed in larger, controlled clinical studies.