Psoriasis is a common inflammatory skin disorder that requires chronic treatment and is associated with multiple comorbidities. Guselkumab, a human immunoglobulin-G1-lambda monoclonal antibody, binds to interleukin-23 with high specificity and affinity and is effective in treating moderate to severe plaque psoriasis. As part of the guselkumab psoriasis clinical trial program, using a confirmatory approach, a population pharmacokinetics (PopPK) model was established using 13 014 PK samples from 1454 guselkumab-treated patients across 3 phase 2/3 trials. Observed serum guselkumab concentrations were adequately described by a 1-compartment linear PK model with first-order absorption and elimination. The final PK model was robust and stable, with apparent clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) estimates of 0.516 L/day, 13.5 L, and 1.11 day-1 , respectively. A model-derived elimination half-life of 18.1 days indicated achievement of steady-state serum guselkumab concentrations within 12-14 weeks. The primary covariate contributing to the observed PK variability was body weight, which accounted for only 28% (CL/F) and 32% (V/F) of the interindividual proportion of variance. Diabetes was identified to marginally reduce guselkumab exposure, owing to 12% higher CL/F in diabetic versus nondiabetic patients, but its contribution was not clinically relevant. None of the other covariates tested (eg, age, sex, ethnicity, immune response to guselkumab, or concomitant medications) had a clinically relevant effect on guselkumab exposure.