Central nervous system (CNS) involvement is an unusual manifestation in multiple myeloma (MM). The molecular basis of CNS myeloma is poorly understood. MM is characterized by translocations involving the immunoglobulin heavy chain (IgH) locus and frequent 13q deletions. Alterations of p53 or c-myc in MM may represent secondary changes associated with disease progression. We investigated nine patients with CNS MM using interphase fluorescence in situ hybridization (FISH) combined with immunofluorescence detection of the cytoplasmic light chain (cIg-FISH) for the presence of above genomic aberrations. Of nine patients studied, eight cases had hemizygous p53 deletion and 4 had 13q deletions. Of the patients with 13q deletions, two had IgH translocations, one involving 4p16.3 (FGFR3), the other involving 16q23 (c-maf). The high incidence of p53 deletions detected by cIg-FISH in CNS myeloma may be a marker for chromosomal instability, and may be associated with metastatic features of myeloma cells.