Current subunit vaccines provide partial protection against pneumonic plague if the infecting Y. pestis strain is encapsulated (F1+). Here we describe YadC, a novel Y. pestis outer membrane protein that provides partial protection against a F1- Y. pestis strain. Swiss-Webster mice were immunized subcutaneously with glutathione S-transferase (GST) or His6-tagged (HT) purified fusion proteins (GST-YadC137-409 or HT-LcrV) or buffer emulsified with Alhydrogel. Intravenous challenge with 1 x 104 F1- Δpgm Y. pestis CO99-3015 revealed no protection for those mice immunized with GST-Alhydrogel alone, full protection for HT-LcrVimmunized mice, and partial protection for GST-YadC137-409 -immunized mice. Similarly, C57BL/6 mice were immunized with GST-YadC137-409, HT-LcrV, or GST all with Alhydrogel adjuvant. After intranasal challenge with 3 x 103 F1- Y. pestis CO99-3015, 87% of GSTYadC137- 409-immunized mice survived pneumonic plague. This is compared to the GST control group (0 surviving mice) and the LcrV-immunized group where 50% survived the challenge. This protection was correlated with a predominantly IgG1 response in LcrV-immunized mice and an IgG1/IgG3 antibody response in YadC-immunized mice. Additionally, we report the cytokine response from HT-LcrV- and GST-YadC137-409-stimulated peripherally derived macrophages. YadC-stimulated cells demonstrated a predominant pro-inflammatory cytokine production. This mixed Th1/Th2 response suggests that YadC's protection may involve a different adaptive immune response than the LcrV protein that currently is part of plague vaccines.