<b><i>Background:</i></b> A significant proliferation of glial cells occurs in the spinal cord and brainstem of SOD1 G93A transgenic mice with familial amyotrophic lateral sclerosis (ALS). Since activated glia may contribute to motor neuron degeneration, we tested whether inhibition of gliosis using low-dose chemotherapy is beneficial in this mouse model. <b><i>Methods:</i></b> Mice were administered fortnightly intraperitoneal injections of 0.1 mg/kg vincristine (VIN) or saline commencing at postnatal day 68 before disease onset. Mice were sacrificed at end-stage disease, and spinal cords were examined for histology. <b><i>Results:</i></b> Survival of VIN-treated mice was significantly increased at 132.0 ± 4.1 days compared to control animals at 117.8 ± 2.1 days (p < 0.05). Furthermore, analysis of microglia and astrocyte populations suggests a reduction in the former following VIN therapy. <b><i>Conclusion:</i></b> This study suggests that chemotherapy may offer an alternative therapy or co-therapy for ALS.