Intracardiac echocardiography (ICE) has emerged as an alternative to transesophageal echo (TEE) to guide left atrial appendage occlusion (LAAO). We established a protocol to select patients appropriate for ICE guidance. Patients who underwent LAAO with the Watchman or Watchman FLX device (Boston Scientific, Marlborough, Massachusetts) from January 2018 to March 2022 at a large United States center were included. The novel protocol prospectively selected TEE or ICE guidance beginning in January 2020; previous LAAO procedures were retrospectively included. ICE was selected for patients with uninterrupted anticoagulation and appropriate LAA anatomy, renal function, and moderate sedation tolerance. In-hospital outcomes with successful implantation without conversion to TEE guidance, no peridevice leak, and no procedural complications were compared. Composite 1-year outcome included freedom from peridevice leak, device-related thrombus, stroke, and all-cause mortality. A total of 234 patients were included; the mean age was 76.1 ± 8.3 years old, and 42.3% were female. ICE guidance was used for 63 procedures; TEE guidance was used for 171 procedures. For the composite outcome, ICE-guided LAAO was superior to TEE-guided LAAO (risk difference 0.102, 96.8% vs 86.5%, 95% confidence interval 0.003 to 0.203, p = 0.029). In comparison to the TEE-guided group, ICE-guided procedures were shorter (89.1 ± 26.3 vs 99.8 ± 30.0 min, p = 0.0087) with less general anesthesia (26.6% vs 98.8%, p <0.0001). One-year composite adverse outcomes did not differ significantly (80.7% vs 88.9%, p = 0.17). In conclusion, the protocol to select appropriate patients for ICE versus TEE guidance for LAAO is safe and effective. Larger studies are indicated to validate this approach to improve outcomes, shorten procedures, and avoid general anesthesia.