Summary Background Cat‐PAD, the first in a new class of synthetic peptide immuno‐regulatory epitopes (SPIREs), was shown to significantly improve rhinoconjunctivitis symptoms in subjects with cat allergy up to 1 year after the start of a short course of treatment. Objective To evaluate the long‐term effects of Cat‐PAD on rhinoconjunctivitis symptoms following standardized allergen challenge 2 years after treatment. Methods In a randomized, double‐blind, placebo‐controlled, parallel group study, subjects were exposed to cat allergen in an environmental exposure chamber (EEC) before and after treatment with two regimens of Cat‐PAD (either eight doses of 3 nmol or four doses of 6 nmol) given intradermally over a 3‐month period. In this follow‐up study, changes from baseline in rhinoconjunctivitis symptoms were reassessed 2 years after the start of treatment. Results The primary endpoint showed a mean reduction in total rhinoconjunctivitis symptom scores of 3.85 units in the 4 × 6 nmol Cat‐PAD group compared to placebo 2 years after the start of treatment (P = 0.13), and this difference was statistically significant in the secondary endpoint at the end of day 4 when the cumulative allergen challenge was greatest (P = 0.02). Consistent reductions in nasal symptoms of between 2 and 3 units were observed for 4 × 6 nmol Cat‐PAD compared to placebo between the 2 and 3 h time points on days 1–4 of EEC challenge at 2 years (P < 0.05). The 8 × 3 nmol dose did not show a meaningful effect in this study. Conclusion and Clinical Relevance A persistent, clinically meaningful reduction in rhinoconjunctivitis symptoms was observed on EEC challenge 2 years after the start of a short course of treatment with 4 × 6 nmol Cat‐PAD. This study is the first to provide evidence of a long‐term therapeutic effect with this new class of SPIREs.