AbstractBackgroundOptical coherence tomography (OCT) and reflectance confocal microscopy (RCM) can yield improved diagnostic accuracy of nonmelanoma skin cancer (NMSC) in comparison with dermoscopy alone.ObjectivesThe aim of this study was to compare the diagnostic performance of OCT and RCM together and individually with that of dermoscopy.MethodsPatients with lesions suspicious for NMSC were randomized into two groups in a prospective, single‐centre study. In the intervention group (IG), every lesion was examined with dermoscopy, OCT and RCM, while in the control group (CG), every lesion was examined with dermoscopy alone.ResultsA total of 365 lesions of 250 patients (105 female, 145 male) were included in the study. A total of 208 basal cell carcinomas (BCCs), 65 squamous cell carcinomas (SCCs) and 31 SCCs in situ were examined histologically. The IG involved significantly fewer biopsies than the CG (14 vs. 27, p = 0.029) and required fewer additional inpatient stays due to positive biopsy results (2 vs. 12, p = 0.001). For the diagnosis of BCC, diagnostic accuracy was 81% with dermoscopy, 84% with OCT, 83% with RCM and 85% with the combination of OCT and RCM (OCT/RCM). The diagnostic accuracy of OCT for BCC subtypes was as follows: superficial, 89%; nodular, 79%; sclerodermiform, 82%; and nodular‐cystic BCC, 75%. For the diagnosis of SCC, diagnostic accuracy was 85% with dermoscopy, 87% with OCT, 89% with RCM and 87% with OCT/RCM. For the diagnosis of in situ SCC, diagnostic accuracy was 87% with dermoscopy, 89% with OCT, 89% with RCM and 91% with OCT/RCM.ConclusionsDiagnostic accuracy increased with OCT and RCM and was even higher when both methods were used together. OCT and RCM could facilitate optimization of lesion management by reducing the number of punch biopsies and reducing additional inpatient stays due to positive biopsy results.