The cholinergic anti-inflammatory pathway offers a proposed mechanism to describe the increased risk of pneumonia following severe traumatic brain injury (sTBI). Vagal activity transmitted to the spleen results in decreased inflammatory cytokine production and immunosuppression. However, no clinical evidence exists. We sought to compare pneumonia rates among patients with TBI and splenectomy using a retrospective analysis of all trauma patients with splenic injury requiring splenectomy or TBI admitted to an ACS verified level one trauma center from 2011 to 2016. Admission Glasgow Coma Score (GCS) ≤ 8 was used to identify sTBI. Pneumonia was defined by respiratory culture obtained by bronchoalveolar lavage. Analysis included χ2 and one-way analysis of variance followed by multivariate logistic regression to determine the association of sTBI and splenectomy of development of pneumonia. Four hundred and twenty-seven patients were included for primary analysis, 247 with sTBI, 180 with splenectomy, and 14 with both sTBI and splenectomy. Rates of pneumonia were increased, although not significant among patients with sTBI and splenectomy and both sTBI alone (71.4 vs. 49.4%, p = 0.11). On multivariate regression, the risk of pneumonia was increased with both splenectomy and sTBI (OR 3.18; 95% CI, 0.75–13.45) and sTBI alone, although significant in the latter only (OR 3.56; 95% CI, 2.12–5.97). Based on these results, splenectomy does not appear to influence the development of pulmonary immunosuppression and pneumonia following sTBI.