Actinic keratosis (AK), a frequently diagnosed cutaneous neoplasm in individuals with chronic sun exposure or fair skin, is a risk factor for squamous cell carcinoma. AK presents as clinically visible lesions and/or as subclinical lesions where an entire field of area (field cancerization) contains lesions of various grades. The diagnosis and surveillance of subclinical AK is challenging. We report a new AK management approach, including subclinical AK, with noninvasive in vivo reflectance confocal microscopy (RCM) monitoring of field-directed topical 5-fluorouracil 0.5%/salicylic acid 10.0% (5-FU/SA; currently approved for single lesions). In this case series, eight patients with primarily recurrent, multiple AKs received ≤ 6 weeks of field-directed 5-FU/SA; complete clearance of clinical/subclinical AKs on various body areas was shown in most patients using RCM. RCM facilitated the detection/characterization of subclinical AKs in the setting of field cancerization. Topical field-directed 5-FU/SA monitored with RCM is a promising management approach for subclinical AKs.