The expression and activation of regulatory factors (IRF) and rinterferon (IFN) response genes were evaluated in a patient treated with autologous hematopoietic stem cell transplant (HSCT) for refractory systemic lupus erythematosus (SLE). In SLE patients, genetic variants of IRF5 and IRF7 have been associated with increased serum IFNα levels, suggesting a pathogenic role in the type I IFN response. Clinical and molecular analyses of an SLE patient treated with high-dose immunosuppressive therapy and autologous stem cell transplant was performed. Western blot analysis showed that induction of IRF7 protein expression correlated with recurrent lupus disease activity. In addition, phosphorylation of IRF3 and activation of 4 E-BP1, a translational repressor of IRF7, preceded the disease flare. In SLE post-transplant, recurrent disease activity and induction of IRF7 protein expression correlated with activation of the IFN signature. This unique trend in regulation of IRF warrants further mechanistic investigation and confirmation with increased numbers of SLE patients.