Glial fibrillary acidic protein (GFAP) is an intermediate filament protein expressed almost exclusively by glial cells of the central nervous system. We have previously transfected GFAP-negative human astrocytoma cells with the gene for GFAP and have demonstrated that GFAP transfection decreases astrocytoma proliferation and alters astrocytoma morphology. To determine if the same cellular responses could be elicited upon GFAP transfection of nonglial tumor cells, in the present study we have transfected a GFAP-negative human malignant fibrosarcoma cell line (HT-1080) with a cDNA containing the entire coding sequence of the human GFAP gene under the control of an inducible metallothionein promoter. Stably transfected HT-1080 clones were identified that are GFAP-positive by PCR and immunocytochemistry. GFAP-positive HT-1080 fibrosarcoma cells also demonstrate a decrease in tumor cell proliferation, altered morphological features characterized by cell elongation and cytoplasmic process formation, and reduction of invasive potential when compared to controls. These findings suggest that the inducible expression of the cytoskeletal protein GFAP can also be associated with dramatic cellular effects in nonglial non-central nervous system tumor cells.