Clinical variants of Frontotemporal dementia (FTD) include semantic dementia (SD) and progressive nonfluent aphasia (PNFA). Together with the closely related disorders FTD with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), they constitute a major cause of young onset dementia. The steroid hormone progesterone (PROG) has an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum samples (39 FTD, 91 controls), low serum PROG was associated with FTD overall (Exp(B) = 2.6, adjusted p = 0.019). In our subgroup analysis, low PROG levels were significantly associated with FTD-MND (N = 12, Exp(B) = 5.0, adjusted p = 0.022) and CBS (N = 10, Exp(B) = 5.9, adjusted p = 0.017), but not with the other subgroups. PROG levels of > 195 pg/mL were significantly correlated with lower disease severity (Frontotemporal dementia rating Scale) for CBS patients (N = 6, standardized β = -0.92, adjusted p = 0.0002). In the human neuroblastoma SK-N-MC cell line, exogenous progesterone (9300 to 93,000 pg/mL) had a significant effect on overall tau and nuclear TDP-43 levels, reducing total tau levels by approximately 1.5 fold (p < 0.05) and increasing nuclear TDP-43 by 1.7 to 2.0 fold (p < 0.05). Finally, elevation of serum PROG to approximately 6000 pg/mL in an Ala315Thr TARDBP mutant mouse model significantly reduced the rate of loss of locomotor control (adjusted p = 0.033) in PROG treated compared with placebo mice. The PROG treatment did not significantly increase survival of the mice, and may be due to the limitation of the transgenic mouse to accurately model TDP-43 mediated neurodegeneration. Nonetheless, our clinical, cellular and animal data provide strong evidence that PROG may be a valid therapy for specific related disorders of FTD.