The reproductive kinetics of Protopolystoma xenopodis primary and secondary infections in Xenopus laevis were monitored in a 3-year study. Thirty-five naïve, lab-raised, full-sib X. laevis from 1 spawning were each exposed to 30 P. xenopodis eggs. The course of infections at 20 °C was monitored by screening isolated hosts for parasite egg production. Ninety-four percent of toads supported the development of gravid parasites. Infections became patent 9–19 weeks p.i., lasted 3–30 months and produced estimated totals of 1–7152 eggs/host. Variation in primary infection characters was discontinuous: a subgrouping of hosts (16%) was characterized by extended infection duration and low reproductive rate. In order to test the effect of long-term infection history on a subsequent challenge, each host was re-exposed to P. xenopodis infective stages (30 eggs/host) 6 months after the loss of its original infection. Establishment of patent infection was significantly lower (15%), and pre-patent period (12–28 weeks) longer, than in primary infections of the same hosts, and than in concurrently exposed naïve controls (contemporary full-sibs of the primary/secondary infection group, maintained in parallel; n = 28). There was no relationship between primary infection characteristics and secondary infection outcome. Overall reproductive output per initial infective stage for the primary exposure exceeded that for the secondary exposure by a ratio of 15[ratio ]1. Results suggest that primary infection with P. xenopodis can elicit strong, long-term protective immunity against re-infection in X. laevis.