BACKGROUND: Photodynamic therapy (PDT) is a recognized treatment for superficial basal cell carcinoma (sBCC). Conventional PDT (C-PDT) has a relatively high clearance rate but is time-consuming and painful. Simulated daylight PDT (SDL-PDT) has the potential advantage of causing less pain, but its effectiveness has not been investigated thoroughly. OBJECTIVES: To determine whether SDL-PDT is non-inferior to C-PDT in the treatment of clinically diagnosed sBCC and to assess adverse events during treatment and patient preferences. METHODS: In this single-centre, non-inferiority, randomized controlled trial, adult patients with sBCCs of any size and located on anatomical sites suitable for PDT were recruited. Lesions were randomized to two sessions of either SDL-PDT or C-PDT using aminolevulinic acid as the photosensitizer. Patient-perceived pain was measured using a numeric rating scale (NRS) ranging from 0 to 10. Self-report forms were used to measure patient preferences. Patients were evaluated after 3 months to assess early treatment failure and after 1 year to determine overall clearance rates. RESULTS: In total, 78 participants with 193 sBCCs were treated. Most lesions (47.2%) were located on the trunk and were diagnosed solely through dermoscopic evaluation (64.2%). After 1 year, the clearance rate was 62.4% for SDL-PDT and 91.8% for C-PDT (p <
0.001) disproving non-inferiority. Illumination was reported to be more painful during C-PDT (mean NRS score of 3.5 at session 1 and 3.7 at session 2) compared with SDL-PDT (mean NRS score of 0.1 at both sessions) (p <
0.001). Immediately after treatment, 87.5% of respondents expressed a preference for SDL-PDT. CONCLUSIONS: SDL-PDT is less effective than C-PDT but is also less painful. Due to the lower clearance rate, this study does not support SDL-PDT as a primary treatment option for sBCC. The randomized controlled trial was registered at http://www.researchweb.org/ (project 264721).