Background: Right ventricular (RV) failure is a critical determinant of survival and prognosis in patients with pulmonary hypertension. Circulating levels of osteopontin (OPN) are increased in these patients and associated with RV remodeling and dysfunction. We hypothesized that OPN-knockout (OPN-KO) mice would be protected from deleterious RV remodeling, and that the reconstitution of OPN using recombinant OPN (rOPN) would abolish the effects of OPN deficiency on the RV in a mouse model of RV failure. Methods: We performed sham or pulmonary artery banding (PAB) surgery in OPN-KO and wild type (OPN-WT) mice and administered rOPN for 3 weeks. Cardiac phenotypes were evaluated with echocardiography and catheterization. Results: PAB surgery caused a significant increase in RV systolic pressure and RV remodeling and dysfunction in both OPN-KO and OPN-WT mice with no differences between them. Treatment with rOPN had no effect on the functional and structural parameters of the RV in either OPN-KO or OPN-WT mice. Interestingly, OPN-KO mice exhibited larger right atrium (RA) dilatation compared to OPN-WT mice, which was attenuated with rOPN treatment. Despite a similar degree of RV remodeling, PAB OPN-KO mice displayed a slightly higher mortality than OPN-WT mice, although this difference was not statistically significant. Treatment with rOPN slightly but not significantly improved the survival of these mice. Conclusions: The lack of OPN did not affect RV remodeling in mice subjected to PAB. However, OPN deficiency was associated with a larger RA dilatation and a higher mortality in PAB mice, which were attenuated with OPN reconstitution. These results suggest that rOPN may have therapeutic potential in treating RV failure.