BACKGROUND: To increase the consultation rate of potential major depressive disorder (MDD) patients, we developed a contact-type fingertip photoplethysmography-based MDD screening system. With the outbreak of SARS-CoV-2, we developed an alternative to contact-type fingertip photoplethysmography: a novel web camera-based contact-free MDD screening system (WCF-MSS) for non-contact measurement of autonomic transient responses induced by a mental task. METHODS: The WCF-MSS measures time-series interbeat intervals (IBI) by monitoring color tone changes in the facial region of interest induced by arterial pulsation using a web camera (1920 x 1080 pixels, 30 frames/s). Artifacts caused by body movements and head shakes are reduced. The WCF-MSS evaluates autonomic nervous activation from time-series IBI by calculating LF (0.04-0.15 Hz) components of heart rate variability (HRV) corresponding to sympathetic and parasympathetic nervous activity and HF (0.15-0.4 Hz) components equivalent to parasympathetic activities. The clinical test procedure comprises a pre-rest period (Pre-R; 140 s), mental task period (MT; 100 s), and post-rest period (Post-R; 120 s). The WCF-MSS uses logistic regression analysis to discriminate MDD patients from healthy volunteers via an optimal combination of four explanatory variables determined by a minimum redundancy maximum relevance algorithm: HF during MT (HF (MT) ), the percentage change of LF from pre-rest to MT (%DeltaLF((Pre-R-->MT)) ), the percentage change of HF from pre-rest to MT (%DeltaHF((Pre-R-->MT)) ), and the percentage change of HF from MT to post-rest (%DeltaHF((MT-->Post-R)) ). To clinically test the WCF-MSS, 26 MDD patients (16 males and 10 females, 20-58 years) were recruited from BESLI Clinic in Tokyo, and 27 healthy volunteers (15 males and 12 females, 18-60 years) were recruited from Tokyo Metropolitan University and RICOH Company, Ltd. Electrocardiography was used to calculate HRV variables as references. RESULT: The WCF-MSS achieved 73% sensitivity and 85% specificity on 5-fold cross-validation. IBI correlated significantly with IBI from reference electrocardiography (r = 0.97, p < 0.0001). Logit scores and subjective self-rating depression scale scores correlated significantly (r = 0.43, p < 0.05). CONCLUSION: The WCF-MSS seems a promising contact-free MDD screening apparatus. This method enables web camera built-in smartphones to be used as MDD screening systems.