Enterovirus (EV)-C105 is a rare genotype not previously detected in Spain. Between 2019 and 2024, we detected EV-C105 in respiratory samples of five patients, through routine EV surveillance. Three cases had respiratory illness and two were hospitalised for neurological illness. Four of the five sequenced strains belonged to an emerging clade (C1), defined by four novel nonsynonymous mutations in key antigenic epitopes. We recommend reinforced clinical awareness and EV genomic surveillance, including respiratory samples, even when symptoms are neurological.