IMPORTANCE: Plaque psoriasis is increasingly managed using anti-inflammatory biologic medications, including tumor necrosis factor (TNF)-α and interleukin (IL) 12/23, IL-17, and IL-23 inhibitors. How these differently priced biologics are used has implications for the overall cost of care in the US. OBJECTIVE: To measure trends in the use and cost of first-line biologic treatments for plaque psoriasis from 2007 to 2021. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study using a national commercial claims dataset (2007-2021) of biologic medication-naive patients with plaque psoriasis who initiated a biologic medication from 1 of 4 mechanistic classes, including 4 TNF-α inhibitors, 1 IL-12/IL-23 inhibitors, 3 IL-17 inhibitors, and 3 IL-23 inhibitors. Data analyses were performed from August 2023 to October 2024. EXPOSURES: Patient demographic characteristics (sex, age, geographic location, insurance type) and clinical characteristics (comorbidities, previous nonbiologic treatments for plaque psoriasis). OUTCOMES: Trends in the proportion of patients initiating each biologic medication and the average estimated annual treatment costs over time, using commercial estimates of net prices accounting for average manufacturer rebates. Logistic regression was used to evaluate demographic and clinical characteristics associated with initiating TNF-α vs IL inhibitors. Estimated savings were calculated for patients who had initiated the lowest-cost treatment within each class. RESULTS: Among 76 781 patients with plaque psoriasis who initiated biologic medications, 50.4% were female and 49.6% male, 71.8% were age 30 to 59 years, and 30% had concurrent inflammatory arthritis. From 2007 to 2021, the proportion of patients initiating IL rather than TNF-α inhibitors increased; in 2021, 42% initiated IL-23 inhibitors and 21% initiated IL-17 inhibitors. The average annual treatment cost increased from $21 236 in 2007 to $47 125 in 2021. In 2021, costs ranged from $12 413 (infliximab) to $70 043 (risankizumab). If patients initiated the lowest-cost medication in each class, the average annual treatment cost would have been 44% lower in 2021 ($26 363). Patients who were male, older, residing in the Northeast, and did not have comorbid arthritis or inflammatory bowel disease had higher odds of initiating IL inhibitors than TNF-α inhibitors. CONCLUSIONS AND RELEVANCE: This cross-sectional study found that from 2007 to 2021, treatment costs increased for biologic medications used to treat plaque psoriasis. Substantial savings are available if more patients and physicians use the lowest-cost options and/or if drug prices were better aligned with the comparative effectiveness and safety of each medication.