Background: This study evaluated glucose control by continuous glucose monitoring (CGM) during treatment with ultra-rapid lispro (URLi) or lispro used in combination with insulin glargine or degludec in adults with type 1 diabetes in a substudy of the PRONTO-T1D study. Methods: Ambulatory glucose profiles were evaluated in 269 patients from PRONTO-T1D assigned to double-blind URLi (n = 97) or lispro (n = 99) given 0-2 min before the start of the meal (mealtime), or open-label URLi (n = 73) given 20 min after the meal (postmeal URLi). Blinded CGM was used for up to 14 days before baseline and the 26-week primary endpoint. The primary objective was to compare mealtime URLi and lispro with respect to incremental area under the serum glucose concentration versus time curve from 0 to 2 h (iAUC(0-2h)) after breakfast. Results: Mealtime URLi was superior in reducing the iAUC(0-2h) when compared to lispro for breakfast (least squares mean [LSM] difference -28.1 mg·h/L, P = 0.048) and for all meals combined. iAUC(0-3h) and iAUC(0-4h) were also reduced. Postmeal URLi resulted in similar postprandial glucose (PPG) control to mealtime lispro, but less optimal PPG control compared to mealtime URLi. Mealtime URLi increased daytime time in range (71-180 mg/dL [3.9-10.0 mmo/L]) (LSM difference = +43.6 min, P = 0.020) and decreased nighttime time in hypoglycemia (LSM difference ≤70 mg/dL [3.9 mmol/L] = -11.5 min, P = 0.009) compared to mealtime lispro. Conclusions: Results of this CGM substudy support the improved PPG control seen with mealtime URLi in the PRONTO-T1D study and show that mealtime URLi resulted in improved daytime time in target range.