Systemic treatments of moderate-to-severe psoriasis differ substantially in terms of effectiveness and costs. Comprehensive economic-evaluations of all systemic treatments for psoriasis from a societal perspective are missing. The objective of our study was to compare the cost-effectiveness all systemic treatments approved for moderate-to-severe psoriasis from a societal perspective, by including all cost categories. An incremental cost-effectiveness-analysis was performed for all systemic treatments for psoriasis, currently recommended by the German S3-Guideline i.e. methotrexate, cyclosporine, fumaric acid esters, and retinoids, adalimumab, etanercept, infliximab and ustekinumab. We used a Markov model with time-dependent transition probabilities and a time horizon of 2 years to investigate incremental cost-effectiveness ratios. Both direct and indirect costs were considered to reflect the societal perspective. Effectiveness outcome was PASI-75 response. One-way and probabilistic sensitivity analyses explored the effect of treatment duration, discount rate, effectiveness, and the perspective (societal vs. healthcare system) on the findings. According to the base-case analysis a cost-effective treatment pathway for moderate-to-severe psoriasis starts with methotrexate, followed by ustekinumab 90 mg and infliximab, if methotrexate does not achieve or maintain PASI-75 response. Sensitivity analyses confirmed the general robustness of these findings with methotrexate being most cost-effective. However, from a third-party-payer perspective (without indirect cost) conventional therapies were generally more cost-effective than biologics. From a value-based healthcare perspective, methotrexate should be the systemic treatment of first choice, ustekinumab 90 mg second choice and infliximab third choice for patients with moderate-to-severe psoriasis. From a societal perspective, the other treatments are less efficient according to our model. From a third-party-payer perspective conventional therapies are more cost-effective than biologics.