The complement system has an important role in the pathogenesis of inflammatory injury and subsequent recovery following ischemic stroke. In the previous award, we identified complement-dependent mechanisms of post-stroke injury and recovery, and we characterized a set of complement inhibitors that are targeted to neoepitopes expressed in the injured brain following stroke. We also determined that complement inhibition significantly improved the outcomes of rehabilitative therapy and thrombolytic therapy, two standards of care. The work proposed here is a continuation of these mechanistic and therapeutic studies, but with a deeper investigation into how complement and complement inhibition interacts with t-PA and rehabilitation therapy (translationally important), while layered on two major stroke comorbidities; ageing and smoking. Cigarette smoke (a patient modifiable risk factor) and age are associated with a higher risk of mortality, more severe disability, longer hospital stays and worse overall functional recovery in stroke patients, and age is also associated with a poorer response to thrombolytic therapy. Military personnel have a significantly higher rate of smoking than the general U.S. population, and it remains significantly higher among older age Veterans and Veterans with diseases such as PTSD, addiction, and HIV. However, despite continuous recommendations from the Stroke Treatment Academic Industry Roundtable (STAIR) committee and funding bodies, few studies have addressed the mechanisms underlying how these comorbidities contribute to worse outcomes. In four specific aims, we propose to: 1. Determine the effects of age and smoking on acute and chronic complement-dependent neuroinflammation after stroke, and investigate the effect of complement modulation in the setting of age and smoking co-morbidities; 2. Determine how complement and a modified neuroinflammatory response induced by age and cigarette smoke exposure interact with the current standards of care t-PA and rehabilitation therapy; 3. Investigate complement inhibition as a chronic treatment strategy for stroke, and the role of complement in both injury and repair chronically; 4. For translational relevance, investigate the correlation between systemic complement activity and serum levels of IgM antibodies and stroke outcomes in acute stroke patients with co-morbidities.