This study aimed to evaluate the efficacy of Invisalign First Phase I treatment compared with tooth-borne rapid maxillary expansion (RME) in mixed dentition patients by examining changes in palatal volume, palatal surface area, and maxillary interdental transverse measurements. In this open-label, 2-arm, parallel, randomized controlled trial, patients with a posterior transverse discrepancy≤6 mm were allocated into the clear aligner therapy (CAT) group (Invisalign First Phase I treatment) and RME group (tooth-borne RME) according to a computer-generated randomization list immediately before the start of treatment. Digital models were obtained before the beginning of the treatment (T0) and at the end of the retention period/treatment (T1) using an intraoral scanner. Palatal volume was measured as the primary outcome, and palatal surface area and intermolar and intercanine transverse widths at the cusps and gingival level were measured as secondary outcomes. Patients and interventionists were not blinded because of the nature of the intervention. Out of 50 patients, 41 (19 males and 22 females; mean age, 8.12 ± 1.53 years) were enrolled and divided into 2 groups: 20 in the CAT group and 21 in the RME group. Two participants did not receive the allocated intervention for different reasons (1 patient discontinued the intervention in the CAT group, and another patient was lost to follow-up in the RME group). Thus, 19 patients (5 males and 14 females; mean age, 8.48 ± 1.42 years) were analyzed from the CAT group, and 20 patients (12 males and 8 females; mean age, 7.83 ± 1.19 years) from the RME group. Regarding intragroup comparisons, all outcome measures significantly increased from T0 to T1 in both groups. In terms of intergroup comparisons, there were no significant differences in the variation (Δ) of outcome measures between the 2 groups from T0 to T1, except for the intermolar width at the gingival level (P<0.005). The change in palatal volume was 532.01 ±540.52 mm³ for the RME group and 243.95 ± 473.24 mm³ for the CAT group (P = 0.084), with a moderate effect size (d = 0.57). RME showed trends favoring better outcomes compared with Invisalign First Phase I treatment across all assessed measures. The only parameter that showed statistically significant differences between the 2 groups was variation in intermolar width at the gingival level, suggesting the occurrence of buccal tipping in patients undergoing Invisalign First Phase I treatment. The trial was registered at ClinicalTrial.gov (no. NCT04760535).