Evolving interactions between predators and prey constitute one of the major adaptive influences on marine animals during the Paleozoic. Crinoids and fish constitute a predator–prey system that may date back to at least the Silurian, as suggested by patterns of crinoid regeneration and spinosity in concert with changes in the predatory fauna. Here we present data on the frequency of breakage and regeneration in the spines of the Middle Devonian camerate Gennaeocrinus and late Paleozoic cladids, as well as an expanded survey of the prevalence of spinosity and infestation by platyceratid gastropods on crinoid genera during the Paleozoic. Spine regeneration frequency in the measured populations is comparable to arm regeneration frequencies from Mississippian Rhodocrinites and from modern deep-water crinoid populations. The prevalence of spinosity varies by taxon, time, and anatomy among Paleozoic crinoids; notably, spinosity in camerates increased from the Silurian through the Mississippian and decreased sharply during the Pennsylvanian, whereas spines were uncommon in cladids until their Late Mississippian diversification. Among camerates, tegmen spinosity is positively correlated with the presence of infesting platyceratid gastropods. These results allow us to evaluate several hypotheses for the effects of predation on morphological differences between early, middle, and late Paleozoic crinoid faunas. Our data corroborate the hypothesis that predators targeted epibionts on camerate crinoids and anal sacs on advanced cladids and suggest that the replacement of shearing predators by crushing predators after the Hangenberg extinction affected the locations of spines in Mississippian camerates.