OBJECTIVES: Dose escalation can increase effectiveness of biologic treatments for plaque psoriasis, but real-world data on usage patterns and associated costs are limited. This study documents real-world patterns and additional costs of above-label use of biologics in patients with plaque psoriasis. METHODS: This was a descriptive, retrospective cohort analysis using the IBM^® MarketScan^® Commercial and Medicare Supplemental Databases. Adult patients diagnosed with plaque psoriasis initiating treatment with etanercept, adalimumab, ixekizumab, or secukinumab between January 1, 2015–November 30, 2019 (index) were eligible. Patients had no other indications for biologics of interest. Outcomes were measured in the 12-month follow-up period after start of maintenance dosing. RESULTS: Of 6453 patients included, 708 (11.0%) received etanercept, 4654 (72.1%) received adalimumab, 228 (3.5%) received ixekizumab, and 863 (13.4%) received secukinumab. Above-label dosing was recorded based on payer databases (excluding use of company samples) in 326 (46.0%) patients receiving etanercept, 513 (11.0%) receiving adalimumab, 40 (17.5%) receiving ixekizumab, and 79 (9.2%) receiving secukinumab. Mean time to above-label use for all treatments was 50.7–99.5 days; the median was 21–37 days. Mean duration of above-label use for all treatments was 130–196 days; the median was 35–175 days. Mean total additional annual psoriasis-related medical/pharmacy costs associated with above-label use were $312/$16,475 for etanercept, $278/$9,773 for adalimumab, $124/$5,202 for ixekizumab, and $277/$9,288 for secukinumab. Above-label use was generally not associated with safety concerns; however, gastrointestinal and combined “other” non-respiratory infections (including urinary tract infection, herpes simplex/oral herpes infections, osteomyelitis, oral candidiasis, conjunctivitis, and cellulitis) were significantly more frequent in patients receiving adalimumab above-label vs on-label. CONCLUSIONS: Above-label use of biologics for psoriasis treatment was most frequent for patients receiving etanercept, followed by ixekizumab, adalimumab, and secukinumab. Above-label vs on-label use resulted in additional costs but few significant safety concerns.