Abstract Background The most frequent pathogen that causes bacterial meningitis is the Gram-positive bacterium Streptococcus (S.) pneumoniae . CCAAT/enhancer binding protein δ is a transcription factor that has recently been hypothesized to play a detrimental role in outcome of meningitis caused by S. pneumoniae . Here, we studied the role of C/EBPδ prior to the development of pneumococcal meningitis. Methods Wild-type and C/EBPδ-deficient mice (C/EBPδ −/− ) were intraveneously infected with S. pneumoniae and sacrificed after 24 or 48 h. cebp δ expression, bacterial loads, inflammatory response and pathology in the brain were assessed. Results S. pneumoniae induces cebp δ expression in the brain during blood-borne brain infection. In comparison to wild-type mice, C/EBPδ −/− animals showed decreased bacterial loads in blood and brain 48 h after inoculation. In the blood compartment, the host inflammatory response was significantly lower upon infection in C/EBPδ −/− mice as compared to wild-type mice. Conclusion C/EBPδ facilitates bacterial dissemination to the brain and enhances the immune response in the blood compartment. Our study suggests that C/EBPδ plays a detrimental role during the initial development of blood-borne brain infection.