Summary Background The persistence and effectiveness of systemic therapies for moderate‐to‐severe psoriasis in current clinical practice are poorly characterized. Objectives To systematically review observational studies investigating the persistence and effectiveness of acitretin, ciclosporin, fumaric acid esters (FAE) and methotrexate, involving at least 100 adult patients with moderate‐to‐severe psoriasis, exposed to therapy for ≥ 3 months. Methods MEDLINE, Embase, the Cochrane Library and PubMed were searched from 1 January 2007 to 1 November 2017 for observational studies reporting on persistence (therapy duration or the proportion of patients discontinuing therapy during follow‐up) or effectiveness improvements in Psoriasis Area and Severity Index (PASI) or Physician's Global Assessment (PGA). This review was registered with PROSPERO, number CRD42018099771. Results Of 411 identified studies, eight involving 4624 patients with psoriasis were included. Variations in the definitions and analyses of persistence and effectiveness outcomes prevented a meta‐analysis from being conducted. One prospective multicentre study reported drug survival probabilities of 23% (ciclosporin), 42% (acitretin) and 50% (methotrexate) at 1 year. Effectiveness outcomes were not reported for either acitretin or ciclosporin. The persistence and effectiveness of FAE and methotrexate were better characterized, but mean discontinuation times ranged from 28 to 50 months for FAE and 7·7 to 22·3 months for methotrexate. At 12 months of follow‐up, three studies reported that 76% (FAE), 53% (methotrexate) and 59% (methotrexate) of patients achieved ≥ 75% reduction in PASI, and one reported that 76% of FAE‐exposed patients achieved a markedly improved or clear PGA. Conclusions The comparative persistence and effectiveness of acitretin, ciclosporin, FAE and methotrexate in real‐world clinical practice in the past decade cannot be well described due to the inconsistency of the methods used. What's already known about this topic? Research examining acitretin, ciclosporin, fumaric acid esters (FAE) and methotrexate for the treatment of moderate‐to‐severe psoriasis has focused on safety and efficacy in randomized controlled trials. The persistence and effectiveness of acitretin, ciclosporin, FAE and methotrexate since the introduction of biologic therapies in real‐world clinical practice are poorly understood. What does this study add? This systematic review examines the persistence and effectiveness of methotrexate, acitretin, ciclosporin and FAE for moderate‐to‐severe psoriasis. Data on the persistence and effectiveness of systemic therapies are lacking, particularly for acitretin and ciclosporin. The definitions of persistence and reporting of effectiveness are inconsistent. Further good‐quality observational studies are needed to explore the real‐world persistence and effectiveness of systemic treatments used for psoriasis. Linked Comment: Garcia-Doval and Sbidian. Br J Dermatol 2019; 181:237. Plain language summary available online