Strategies that block infiltration of leukocytes into the injured spinal cord improve sparing of white matter and neurological recovery. In this article, we examine the dependency of recovery on hematogenous depletion of neutrophils and monocytes. Mice were depleted of neutrophils or monocytes by systemic administration of anti-Ly6G or clodronate-liposomes. A third group was depleted of both subsets. Neurological improvement, based on a battery of tests of performance, and white matter sparing, occurred only in animals depleted of both neutrophils and monocytes. We also attempted to define the nature of the environment that was favorable to recovery. Hemeoxygenase-1 and malondialdehyde, markers of oxidative stress and lipid peroxidation, respectively, were reduced to similar levels in animals depleted of both neutrophils and monocytes, or only monocytes, but remained elevated in the group only depleted of neutrophils. Matrix metalloproteinase-9, a protease involved in early damage, was most strongly reduced in animals depleted of both leukocyte subsets. Finally, disruption of the blood-spinal cord barrier and abnormal nonheme iron accumulation were reduced only in animals depleted of both neutrophils and monocytes. Together, these findings indicate cooperation between neutrophils and monocytes in mediating early pathogenesis in the contused spinal cord and defining long-term neurological recovery.