Background: Automated insulin delivery systems are associated with improved glycemic outcomes for patients with diabetes. Ultrarapid lispro (URLi), which has an accelerated pharmacokinetic profile and shows superior postprandial glucose control compared to lispro (Humalog(®)), is a potential candidate for use in these systems. Methods: In this double-blind, crossover trial over two 4-week treatment periods, we evaluated URLi in a hybrid closed-loop system using the Medtronic MiniMed™ 670G system (670G). After a 2-week lead-in on lispro, 42 adults with type 1 diabetes were randomized to 1 of 2 treatment sequences of URLi and lispro delivered via the 670G. Primary endpoint was the percentage of time with glucose values within target range 3.9-10.0 mmol/L (70-180 mg/dL; %TIR). Results: Both treatments achieved %TIR over the 24-h period that was above the 70% minimum recommended by the International Consensus Guidance: URLi, 77.0%; lispro, 77.8%; P = 0.339. %Time <3.0 mmol/L (54 mg/dL) was similar between treatments (URLi, 0.3%; lispro, 0.4%; P = 0.548) and %time <3.9 mmol/L (70 mg/dL) was lower with URLi (1.5%) versus lispro (2.2%); P = 0.009, while %time >10.0 mmol/L (180 mg/dL) was higher with URLi (21.5% [309.4 min] vs. 19.9% [287.2 min]; P = 0.088). Mean sensor glucose was significantly higher with URLi versus lispro with least squares mean difference of 0.17 mmol/L or 3.0 mg/dL (P = 0.011) between treatments. Insulin dose, %time in Auto Mode per week, and pump settings were similar between treatments. No serious adverse events (AEs) (including severe hypoglycemia) or discontinuations occurred, and the incidence of treatment-emergent AEs was similar between treatments. Although the overall incidence and rate of unplanned infusion set changes were similar between treatments, a significantly higher rate of unplanned infusion set changes due to infusion site reactions was seen during URLi treatment compared with lispro: 0.12 versus 0.00 events/30 days (P = 0.063). Conclusions: URLi demonstrated good glycemic control that was comparable to lispro and showed a similar safety profile to lispro with the 670G hybrid closed-loop system. Trial registration: ClinicalTrials.gov, NCT03760640.