Background Primary sclerosing cholangitis (PSC) represents 5% of the indications for liver transplantation (LT). Recurrence of PSC (rPSC) is reported to occur in 8-27% and it has a great impact on both graft and patient survival. Methods the clinical data of 35 patients with PSC who underwent LT at our center in the last 20 years were retrospectively evaluated. Twentyfive were male (71,4%) with a history of IBD before OLT (67%). Tacrolimus+steroid was the most frequent immunosoppressive schedule (84.8%). Five patients (15.1%) underwent re-OLT (3 for rPSC, 2 for immunological damage). Graft and patient survival at 5 years were 73.6% and 88%. A female transplanted for the first time at the age of 17 years, redeveloped aggressive rPSC, with the need for a third LT. The time interval between second and third LT was much shorter than between the first and second LT (2015-2019-2021). In order to modulate the patient's immune reactivity, within 3 months from the 3rdLT, stem cell mobilization (cyclophosphamide+G-CSF) was performed, and CD34+ cells were selected: the patient eventually underwent autologous hematopoietic stem cell transplantation (aHSCT), preceded by a conditioning regimen (melphalan+rabbit antithymocyte globulin). In the immediate post-aHSCT, the patient experienced a E. Coli-related sepsis. The full immunosuppressive regimen was reintroduced 18days after aHSTC. Three and 14 months after aHSCT, she underwent follow-up liver biopsies which excluded rPSC and showed a picture of mild ectasia of centrolobular veins and pericentral sinusoids, associated with initial aspects of sclero-atrophy of the bile ducts, consistent with liver injury secondary to chemotherapy. Liver test were maintained normal. Conclusion ReLT is the only treatment option for aggressive rPSC. Our patient succesfully underwent 3rd R-LT combined with aHSCT with no evidence of rPSC at over 14 months follow-up: this may represent a successful approach as a preemptive strategy in selected cases of reLT for rPSC. Primary sclerosing cholangitis (PSC) represents 5% of the indications for liver transplantation (LT). Recurrence of PSC (rPSC) is reported to occur in 8-27% and it has a great impact on both graft and patient survival. the clinical data of 35 patients with PSC who underwent LT at our center in the last 20 years were retrospectively evaluated. Twentyfive were male (71,4%) with a history of IBD before OLT (67%). Tacrolimus+steroid was the most frequent immunosoppressive schedule (84.8%). Five patients (15.1%) underwent re-OLT (3 for rPSC, 2 for immunological damage). Graft and patient survival at 5 years were 73.6% and 88%. A female transplanted for the first time at the age of 17 years, redeveloped aggressive rPSC, with the need for a third LT. The time interval between second and third LT was much shorter than between the first and second LT (2015-2019-2021). In order to modulate the patient's immune reactivity, within 3 months from the 3rdLT, stem cell mobilization (cyclophosphamide+G-CSF) was performed, and CD34+ cells were selected: the patient eventually underwent autologous hematopoietic stem cell transplantation (aHSCT), preceded by a conditioning regimen (melphalan+rabbit antithymocyte globulin). In the immediate post-aHSCT, the patient experienced a E. Coli-related sepsis. The full immunosuppressive regimen was reintroduced 18days after aHSTC. Three and 14 months after aHSCT, she underwent follow-up liver biopsies which excluded rPSC and showed a picture of mild ectasia of centrolobular veins and pericentral sinusoids, associated with initial aspects of sclero-atrophy of the bile ducts, consistent with liver injury secondary to chemotherapy. Liver test were maintained normal. ReLT is the only treatment option for aggressive rPSC. Our patient succesfully underwent 3rd R-LT combined with aHSCT with no evidence of rPSC at over 14 months follow-up: this may represent a successful approach as a preemptive strategy in selected cases of reLT for rPSC.