Orbital-optimized MP2.5 [or simply "optimized MP2.5," OMP2.5, for short] and its analytic energy gradients are presented. The cost of the presented method is as much as that of coupled-cluster singles and doubles (CCSD) [O(N-6) scaling] for energy computations. However, for analytic gradient computations the OMP2.5 method is only half as expensive as CCSD because there is no need to solve lambda(2)-amplitude equations for OMP2.5. The performance of the OMP2.5 method is compared with that of the standard second-order Moller-Plesset perturbation theory (MP2), MP2.5, CCSD, and coupled-cluster singles and doubles with perturbative triples (CCSD(T)) methods for equilibrium geometries, hydrogen transfer reactions between radicals, and noncovalent interactions. For bond lengths of both closed and open-shell molecules, the OMP2.5 method improves upon MP2.5 and CCSD by 38%-43% and 31%-28%, respectively, with Dunning's cc-pCVQZ basis set. For complete basis set (CBS) predictions of hydrogen transfer reaction energies, the OMP2.5 method exhibits a substantially better performance than MP2.5, providing a mean absolute error of 1.1 kcal mol(-1), which is more than 10 times lower than that of MP2.5 (11.8 kcal mol(-1)), and comparing toMP2 (14.6 kcal mol(-1)) there is a more than 12-fold reduction in errors. For noncovalent interaction energies (at CBS limits), the OMP2.5 method maintains the very good performance of MP2.5 for closed-shell systems, and for open-shell systems it significantly outperforms MP2.5 and CCSD, and approaches CCSD(T) quality. The MP2.5 errors decrease by a factor of 5 when the optimized orbitals are used for open-shell noncovalent interactions, and comparing to CCSD there is a more than 3-fold reduction in errors. Overall, the present application results indicate that the OMP2.5 method is very promising for open-shell noncovalent interactions and other chemical systems with difficult electronic structures. (C) 2014 AIP Publishing LLC.