Laser ablation offers a procedure for precise, fast and minimally invasive removal of superficial and early nodular basal cell carcinomas (BCCs). However, the lack of histopathological confirmation has been a limitation toward widespread use in the clinic. A reflectance confocal microscopy (RCM) imaging-guided laser ablation approach offers cellular-level histopathology-like feedback directly on the patient, which may guide and help improve the efficacy of this procedure. We performed an initial study on 44 BCCs on 21 patients in vivo (based in an ex vivo bench-top study reported in our earlier papers), using a pulsed erbium: ytterbium aluminum garnet laser and a contrast agent (aluminum chloride). Initial 10 lesions, the RCM imaging-guided detection of either presence of residual tumor or complete clearance was immediately confirmed with histopathology. Additionally, 34 BCCs on 15 patients were treated with RCM imaging-guided laser ablation, and the clearance of tumor is currently being monitored with follow-up imaging (i. e., no histopathology) at 3, 6 and 18 months. Thus far, the imaging resolution appears to be sufficient and consistent for monitoring efficacy in the wound, both immediately post-ablation and subsequently during recovery. The efficacy appears to be promising. However, further investigation and optimization to image over the entire wound (without missing any areas) need to be investigated.