This study investigated effects of anti-oligomeric antibodies on AD neuropathology and cognitive deficits in 3xTg-AD mice. Immunization against Aβ has offered a promising approach toward the therapeutic management of AD. Promising pre-clinical findings led to clinical trials with a synthetic Aβ42 vaccine, but further development was halted when 6% of immunized patients developed meningoencephalitis. Direct administration of anti-Aβ antibodies is believed to represent a safer alternative that minimizes the risk of a proinflammatory T cell response and permitting dosage control. Recent pre-clinical studies illustrate that passive immunization with antibodies that target amyloid plaques also increase cerebral amyloid angiopathy (CAA) and CAA-associated microhemorrhage in transgenic mouse models of AD, so anti-oligomeric antibodies were used in this study and showed significantly reduced amyloid load and improved cognition. The clearance of amyloid load was significantly correlated with reduced tau hyperphosphorylation and improvement in cognition. These results demonstrate that systemic immunotherapy using oligomer-specific monoclonal antibodies effectively attenuates behavioral and pathological impairments in 3xTg-AD mice. These findings demonstrate the potential of using oligomer specific monoclonal antibodies as a therapeutic approach to prevent and treat Alzheimer’s disease.