BACKGROUND: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) Study is a prospective analysis of an international database and here we examine front-line treatments and quality-of-life in patients with newly diagnosed Mycosis Fungoides (MF).OBJECTIVES: a) differences in first-line approach according to the TNMB staging; b) parameters related to a first-line systemic approach; c) response rates and quality of life (QoL) measures.PATIENTS AND METHODS: 395 newly diagnosed patients with early-stage MF (IA-IIA) were recruited from 41 centers in 17 countries between 1/1/2015-31/12/2018 following central clinicopathological review.RESULTS: First-line therapy was skin directed therapy (SDT) (81.6%) whilst a smaller percentage (44 cases;11.1%) received systemic therapy. Expectant observation was 7.3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA: 6%; IB: 14%; IIA:20%; IA-IB vs IIA: p<0.0001), presence of plaques (T1a+T2a: 5%; T1b+T2b: 17%; p<0.001), higher mSWAT (>10: 15%; <=10: 7%; p=0.01) and folliculotropic MF (FMF) (24% vs 12%; p=0.001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs T1a/T2a: OR: 3.07) and FMF (OR: 2.82). The overall response rate (ORR) to first-line SDT was 73% whilst the ORR to first-line systemic treatments was lower (57%) (p=0.027). Health related QoL improved significantly in both patients with responsive and stable disease.CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices and that SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early-stage MF need to address these issues.