Subacute sclerosing panencephalitis (SSPE) is a rare complication of measles characterized by progressive neurological deterioration. The onset usually occurs about seven to 10 years after the measles infection. Aside from an earlier age of measles infection, factors that may influence the susceptibility for its development is unknown. There is a paucity of data regarding the course of SSPE in the presence of concomitant autoimmune conditions such as systemic lupus erythematosus (SLE). We report a case of a 19-year-old female who presented with new onset recurrent generalized tonic-clonic seizures, malar rash, and cutaneous erythematous, maculopapular eruptions. Antinuclear antibodies (ANA) and anti-double stranded DNA (anti-dsDNA) serologic examination yielded positive results favoring the diagnosis of SLE. Further in the course of illness, the patient developed generalized myoclonic jerks and progressive decline in language, cognitive, and motor functions. Subsequent investigation showed an elevated anti-measles antibody titer in the cerebrospinal fluid, and periodic generalized, bilaterally synchronous, and symmetric high voltage slow-wave complexes in the EEG. These findings and the typical evolution of neurologic manifestations fulfilled two major and one minor Dyken’s criteria for the diagnosis of SSPE.It is postulated that some autoimmune-mediated responses may contribute to the evolution of SSPE. Autoimmune complexes in SLE induce downregulation of T-cell responses which accelerate the loss of antibodies formed against other diseases such as the measles virus that may lead to increased susceptibility to infection. SSPE is hypothesized to result from the downregulation of host-immune responses which leads to incomplete measles viral clearance. To the best of the authors’ knowledge, this is the first published case of SSPE with active SLE.