Sequential digital dermoscopy (SDD) is applied for early melanoma detection by uncovering dynamic changes of monitored lesions. Convolutional neural networks (CNN) are capable of high diagnostic accuracies similar to trained dermatologists. To investigate the capability of CNN to correctly classify melanomas originally diagnosed by mere dynamic changes during SDD. A retrospective cross-sectional study using image quartets of 59 high-risk patients each containing one melanoma diagnosed by dynamic changes during SDD and three nevi (236 lesions). Two validated CNN classified quartets at baseline or after SDD follow-up at the time of melanoma diagnosis. Moreover, baseline quartets were rated by 26 dermatologists. The main outcome was the number of quartets with correct classifications. CNN-1 correctly classified 9 (15.3%) and CNN-2 8 (13.6%) of 59 baseline quartets. In baseline images, CNN-1 attained a sensitivity of 25.4% (16.1%–37.8%) and specificity of 92.7% (87.8%–95.7%), whereas CNN-2 of 28.8% (18.8%–41.4%) and 75.7% (68.9%–81.4%). Expectedly, after SDD follow-up CNN more readily detected melanomas resulting in improved sensitivities (CNN-1: 44.1% [32.2%–56.7%]; CNN-2: 49.2% [36.8%–61.6%]). Dermatologists were told that each baseline quartet contained one melanoma, and on average, correctly classified 24 (22–27) of 59 quartets. Correspondingly, accepting a baseline quartet to be appropriately classified whenever the highest malignancy score was assigned to the melanoma within, CNN-1 and CNN-2 correctly classified 28 (47.5%) and 22 (37.3%) of 59 quartets, respectively. The tested CNN could not replace the strategy of SDD. There is a need for CNN capable of integrating information on dynamic changes into analyses. • Differentiating early melanomas from atypical nevi is challenging. • Sequential digital dermoscopy helps to uncover the dynamic changes in early melanomas. • CNN are equally accurate at diagnosing skin cancer than trained dermatologists. • The CNN of our study may not replace the strategy of sequential digital dermoscopy. • Development of CNN, including information on lesion evolution, seems indispensable. [ABSTRACT FROM AUTHOR]