Background: Community acquired pneumonia (CAP) is a life-threatening lung infection and the most common reason for hospital admission. Both COVID-19 and non-COVID-19 CAP trigger inflammatory and thrombotic host responses driving morbidity and mortality. In non-critically ill patients hospitalized for COVID-19, therapeutic-dose heparin improves survival and reduces intensive care unit (ICU)-level organ support. Antiplatelet agents may also favorably modulate host responses; however, their role in COVID-19 and non-COVID-19 CAP remains uncertain. Objectives: The overall objective was to evaluate the treatment effects and safety of antiplatelet agents and their interactions with therapeutic-dose heparin in CAP. Specifically, we aimed to meta- analyze the effect of antiplatelet agents in non-COVID-19 CAP, and to evaluate the effect of combination antiplatelet agents with therapeutic-dose heparin in COVID-19 CAP. Methods: We conducted a systematic review/meta-analysis of observational studies and randomized controlled trials (RCTs) of hospitalized patients with non-COVID-19 CAP evaluating the effect of antiplatelet agents (ASA or P2Y12 inhibitors) on mortality. We conducted a secondary analysis of the multiplatform trial (mpRCT) to evaluate the effect of combination antiplatelet agents with therapeutic-dose heparin compared to therapeutic-dose heparin alone in COVID-19. Results: We meta-analyzed 13 observational studies and 2 RCTs in our systematic review. In observational studies reporting hazard ratio (HR), antiplatelet agents were associated with lower mortality (HR 0.65, 95% CI 0.46-0.91; I2 85%; 4 studies, 91,430 patients). In studies reporting adjusted odds ratio (aOR), antiplatelet agents were associated with reduced odds of mortality (aOR 0.67, 95% CI 0.45 – 1.00, I2 0%; 2 studies, 24,899 patients). Among RCTs there was a non- significant association with mortality (risk ratio 0.66, 95% CI 0.20 – 2.25; I2 54%, 2 studies, 225 patients). In our secondary analysis of the mpRCT, 1,021 patients hospitalized with COVID-19 received therapeutic-dose heparin, of which 19% concurrently received an antiplatelet agent. Combination treatment was not associated with an improvement in survival without the need for organ support (OR 1.07, 95% CI 0.71 – 1.64). Conclusions: Antiplatelet agents may be associated with reduced mortality in hospitalized patients with non-COVID-19 CAP, but the certainty of the evidence was low. Exposure to combination antiplatelet and therapeutic-dose heparin in COVID-19 did not improve outcomes. This thesis has provided foundational work to inform the design of a future RCT of antiplatelet agents in CAP.