Platelet-dense (δ) granules are important for platelet function. Platelets contribute to host defense and vascular integrity during pneumonia and sepsis, and δ granule products, including adenosine diphosphate (ADP), can influence inflammatory responses. We therefore aimed to study the role of platelet δ granules in the host response during sepsis. Hermansky-Pudlak syndrome <i>(Hps)3coa</i> mice (with reduced δ granule content), mice treated with the platelet ADP receptor inhibitor clopidogrel, and appropriate control mice were infected with the human sepsis pathogen <i>Klebsiella pneumoniae</i> via the airways to induce pneumonia and sepsis. In order to override potential redundancy in platelet functions, we also studied <i>Hps3coa</i> and control mice with moderate antibody-induced thrombocytopenia (10%) prior to infection. We found that sepsis-induced thrombocytopenia tended to be less severe in <i>Hps3coa</i> mice, and was significantly ameliorated in <i>Hps3coa</i> mice with low pre-infection platelet counts. Bacterial growth was similar in <i>Hps3coa</i> and control mice in the presence of normal platelet counts prior to infection, but lower in the lungs of <i>Hps3coa</i> mice with low pre-infection platelet counts. <i>Hps3coa</i> mice had unaltered lung pathology and distant organ injury during pneumosepsis, irrespective of pre-infection platelet counts; lung bleeding did not differ between <i>Hps3coa</i> and control mice. Clopidogrel did not influence any host response parameter. These data suggest that platelet δ granules can play a detrimental role in pneumosepsis by aggravating thrombocytopenia and impairing local antibacterial defense, but that these unfavorable effects only become apparent in the presence of low platelet counts.