The aim of this study was to analyse the SPRN genes of goats from several scrapie outbreaks in order to detect polymorphisms and to look for association with scrapie occurrence, by an unmatched case-control study. A region of the caprine SPRN gene encompassing the entire ORF and a fragment of the 3'UTR revealed a total of 11 mutations: 10 single-nucleotide polymorphisms and one indel polymorphism. Only two non-synonymous mutations occurring at very low incidence were identified. A significant association with scrapie positivity in the central nervous system was found for an indel polymorphism (602_606insCTCCC) in the 3'UTR. Bioinformatics analyses suggest that this indel may modulate scrapie susceptibility via a microRNA-mediated post-transcriptional mechanism. This is the first study to demonstrate an association between the SPRN gene and goat scrapie. The identified indel may serve as a genetic target other than PRNP to predict disease risk in future genetics-based scrapie-control approaches in goats.