Background <p>Family history (FH) of psoriasis has been implicated as a risk factor for developing psoriasis. However, whether FH also carries information on clinical presentation and treatment response to biological agents in patients with psoriasis remains unclear.</p> Objective <p>This prospective, multicenter observational study aimed to analyze the clinical presentation and efficacy differences between patients with psoriasis with and without a FH.</p> Patients and Methods <p>The SPEECH registry is an observational, multicenter, and prospective registry that has been collecting data on psoriasis treatment since November 2022. This study included adult patients diagnosed with moderate-to-severe plaque psoriasis initiating treatment with biologics, including guselkumab, secukinumab, ixekizumab, ustekinumab, and adalimumab. FH of psoriasis was identified through patient self-report in which a positive FH was defined as a first-degree relative having psoriasis. The primary outcome measures include 75% improvement in Psoriasis Area and Severity Index (PASI75) and the Physician’s Global Assessment score of cleared/minimal (PGA 0/1) after 3 months of treatment. Logistic regression was employed to determine the adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the achievement of response in selected outcomes for patients with a FH compared with those without a FH.</p> Results <p>The study included a total of 859 patients, of whom 22.9% had a FH of psoriasis. Patients with psoriasis who had a FH experienced an earlier onset of the disease and more severe anxiety symptoms than those without a FH. After 3 months of treatment, patients with psoriasis with a FH exhibited a higher likelihood of achieving PASI75 (aOR 1.60 [95% CI 1.02, 2.51]) and PGA 0/1 (aOR 1.54 [95% CI 1.03, 2.31]). Notably, these differences persisted after 6 months of treatment, confirming the sustained effectiveness of biologic treatments in patients with a positive FH. Further mediation analysis uncovered a significant indirect effect of FH on the treatment response to biologics through age of onset (<i>p</i> = 0.028), and the proportion mediated was 20.5%.</p> Conclusion <p>FH of psoriasis may affect the clinical course of patients and enhance their treatment response to biologics, highlighting the importance of FH assessment in optimizing treatment outcome and guiding clinical decision of biologic selection. Future studies on biologic treatment responses in psoriasis should consider family history as a significant confounding factor.</p> Chinese Clinical Trial Registry <p>ChiCTR2000036186.</p>