Abstract Dupilumab is the only FDA-approved systemic therapy for prurigo nodularis (PN), however, immunosuppressants (IS) and phototherapy have been used off-label for the treatment of this condition. Patients with prior IS/phototherapy treatment may represent a more severe and/or treatment-refractory population of patients with PN. Report post-hoc efficacy of dupilumab in patients with PN, with or without prior use of IS or phototherapy for PN. LIBERTY-PN PRIME and PRIME2 (NCT04183335 and NCT04202679) are randomized, 24-week, phase 3 studies in adults with PN that is inadequately controlled by topical prescription therapies or for whom those therapies are not advisable. Primary outcomes included a ≥4-point improvement in the weekly average of Worst Itch Numerical Rating Scale (WI-NRS) from baseline to week 24, and an Investigator’s Global Assessment for PN stage (IGA PN-S) score of 0/1 (clear/almost clear) at week 24. Safety outcomes included the incidence of treatment-emergent adverse events (TEAEs). Among patients with PN, 8.0% reported prior use of phototherapy, and 36.7% reported prior use of IS; overall, 126 (dupilumab group, n = 62; placebo group, n = 64) patients with and 185 (dupilumab, n = 91; placebo, n = 94) patients without prior IS/phototherapy use were included. A larger proportion of patients with prior treatment vs. patients without prior treatment had severe disease, as measured by IGA PN-S (40.5% vs. 29.0%). The baseline WI-NRS score (SD) for overall patients with prior treatment was 8.6 (1.0) and for patients without prior treatment was 8.4 (1.0). At week 24, 67.7% vs. 15.6% of patients in the dupilumab vs. placebo groups with prior treatment (odds ratio [95% confidence interval]: 13.6 [3.7–49.7]; P < 0.0001), and 52.7% vs. 21.3% of patients without prior treatment (5.8 [2.4–14.0]; P < 0.0001) achieved improvement in WI-NRS. Similarly, 35.5% vs. 10.9% (3.1 [1.2–8.4]; P = 0.0162) of patients with and 53.8% vs. 21.3% (5.0 [2.3–10.8]; P < 0.0001) of those without prior treatment achieved IGA PN-S score of 0/1, respectively. TEAEs were reported by 43 (69.4%) vs. 34 (53.1%) patients (dupilumab vs. placebo groups) with and 54 (60.0%) vs. 55 (59.1%) without prior treatment, respectively. Patients treated with dupilumab experienced a greater and clinically meaningful improvement in itch and achieved skin that was clear/almost clear of nodules at week 24, regardless of prior use of IS/phototherapy for the treatment of PN. The incidence of TEAEs was generally consistent among patients with and without prior IS/phototherapy.