Previously, we showed that triggering the extrinsic apoptotic pathway by up-regulating activation-induced cell death (AICD) is a very effective way to kill CTCL cells in-vitro and ex-vivo (J Invest Dermatol. 2015; 135: 861-8). To identify novel small molecules that induce extrinsic apoptosis in CTCL, we used CTCL line HH in an ELISA assay to detect cleaved caspase 8 induced by 1710 unique compounds in the NIH Clinical Collection, Selleck Kinase Inhibitor Library and Prestwick Chemical Library. As assessed by Annexin V/PI flow cytometry of HH, the non-prescription topical antimicrobial remedy, gentian violet (GV), induced more total apoptosis than mechlorethamine (FDA-approved for topical therapy of CTCL). Furthermore, GV induced roughly 4-6X greater apoptosis in CTCL lines (MyLa, SeAx, Hut78, HH, SZ4) than in normal keratinocytes, suggesting a favorable topical toxicity profile. In addition to increasing caspase 8, GV also upregulated death receptors DR4, DR5 and ligands TRAIL, FASL. This is consistent with induction of extrinsic apoptosis via the TRAIL and FAS pathways. Increased phosphorylation of phospholipase C-gamma 1, Ca++ influx and ROS were also detected in CTCL lines, indicating the mechanism of FASL upregulation involves key elements of the AICD pathway. Methotrexate significantly increased GV apoptosis in Sezary blood cells and all CTCL lines tested except FAS-null SeAx, suggesting the role of FAS in this process. In ex-vivo studies, 1μM GV induced up to 90% CTCL apoptosis in Sezary blood cells. GV also reduced expression of anti-apoptotic MCL-1 and pro-proliferative NFkB components while increasing IkB levels that promote NFkB catabolism. Furthermore, GV inhibited cell proliferation and induced cell cycle arrest. Although purple at neutral pH, GV can be rendered colorless by altering its pH. These preclinical findings broaden our knowledge of the anti-neoplastic effects of GV and provide a rationale for clinical studies of its utility as a novel inexpensive topical therapy for CTCL.