Abstract Background Patients with psoriasis affecting a low percentage of their body surface area (BSA) are underrepresented in clinical studies and may face substantial disease burden if high-impact sites are affected. Objectives SPECTREM is a Phase 3b, randomized, placebo-controlled study evaluating guselkumab efficacy and safety in participants with low BSA (2%-15%), moderate (Investigator’s Global Assessment [IGA]=3) plaque psoriasis involving ≥1 high-impact site (scalp, face, genitals, intertriginous areas). Methods Eligible participants were randomized 2:1 to receive guselkumab 100 mg or placebo at Week 0 and Week 4, then every 8 weeks. The primary endpoint was the proportion of participants achieving IGA 0/1 (cleared/minimal) at Week 16. Major secondary endpoints included the proportion of participants achieving ≥90% improvement in Psoriasis Area and Severity Index (PASI 90), IGA 0, and PASI 100; mean percent improvements from baseline to Week 16 in BSA and PASI; and proportions of participants achieving site-specific IGA or Physician’s Global Assessment (PGA) 0/1 among those with scalp, facial, genital, or intertriginous site-specific IGA/PGA ≥3 at baseline. Results Among the 338 (guselkumab, n=225; placebo, n=113) randomized participants, mean (SD) baseline BSA was 7.6% (3.7) and PASI was 9.0 (3.8). At Week 16, all primary and major secondary endpoints were met, with guselkumab demonstrating superiority versus placebo (all p<0.001) in the proportions of participants achieving IGA 0/1 (74.2% vs 12.4%), IGA 0 (40.4% vs 3.5%), PASI 90 (52.9% vs 6.2%), and PASI 100 (32.4% vs 2.7%), and mean percent improvement from baseline in BSA (80.6% vs 6.1%) and PASI (82.6% vs 13.7%). Site-specific IGA/PGA 0/1 response rates for guselkumab versus placebo were: scalp, 75.0% (114/152) versus 14.5% (11/76); face, 87.8% (79/90) versus 28.6% (12/42); genital, 78.0% (64/82) versus 37.5% (15/40); and intertriginous, 86.5% (96/111) versus 28.8% (15/52). In the guselkumab and placebo groups, respectively, 37.8% and 39.8% experienced ≥1 adverse event; no new safety signals were identified. Conclusions Through Week 16, guselkumab was effective and well tolerated in participants with low BSA, moderate plaque psoriasis with involvement of high-impact sites. Statistically significant improvements across multiple clearance measures, irrespective of baseline BSA, support the effectiveness of guselkumab across a broad range of patients. ClinicalTrials.gov Identifier NCT06039189