Engraftment failure and graft versus host disease (GVHD) are major obstacles to success of non-myeloablative allogeneic stem cell transplantation. Whole body UVB phototherapy has been used for the treatment of skin GVHD and has systemic immunosuppressive effects. In addition, extracorporeal photopheresis (ECP) has been used for treatment and prevention of GVHD. We hypothesized that whole body UVB phototherapy may have immunosuppressive effects similar to ECP and improve donor engraftment and reduce the incidence and severity of GVHD. The aim of this study was to test the feasibility of using UVB phototherapy initiated prior to grafting and continued until engraftment and determine its impact on transplant outcome. Eight patients median age 55.5 (range 32–65) years with hematological malignancies who were >55 years of age or had received prior autologous or allogeneic transplantation with myeloablative conditioning or had comorbid conditions that precluded their eligibility for myeloablative transplantation were included in this study. The graft source was matched related (n=5) or matched unrelated (n=3) donor allogeneic peripheral blood stem cells. All donors were male, median age (range) 59 (46–67) years. Conditioning regimen was fludarabine 30 mg/m2 iv for 5 days (days −8 to −4); cyclophosphamide 1 g/m2/day iv for 2 days (days −3 to −2); equine anti-thymocyte globulin (ATG) 30 mg/kg/day for 2 days (days −2 to −1). GVHD prophylaxis included cyclosporine A (CSA), methylprednisolone and escalating doses of UVB to skin tolerance 3 times a week between T-10 and T+28. The conditioning regimen and the UVB phototherapy were well tolerated. Two patients received all 14 prescribed UVB (cummulative doses 2000 and 3260 mJ) and, six patients received 8–13 treatments (cummulative dose range of 528–3465 mJ). Neutrophil (>500ml) and platelet recovery (>20,000/ml) occurred in median of 13 (12–17) and 6.5 days (1–35), respectively. One patient had secondary engraftment failure and another had mixed chimerism at day 100. Seven of eight patients developed severe acute GVHD, Grade III (n=5) and IV (n=2). Six had skin, 5 had GI and 1 had liver involvement. Four patients died from sepsis (n=2), acute GVHD (n=1), or chronic GVHD (n=1). The protocol was closed early due to high severe GVHD rate (87.5%, 95%CI: 60–92%) that satisfied the early-stopping rule. Four patients are alive (130–287 days), 2 without GVHD or relapse. We conclude that addition of peritransplant UVB phototherapy using the standard minimally erythemogenic protocol is detrimental to outcome of allogeneic stem cell transplantation. It is unclear how UVB phototherapy at immunsupressive doses might have altered skin and systemic cytokine and immune cell composition in the host and increased the incidence of GVHD and the treatment related mortality. Therefore although other phototherapeutic modalities may be effective against GVHD, UVB therapy is not recommended during early phases of reduced conditioning allogeneic transplantation.