Brain damage in acute sepsis may be associated with poor long-term outcomes that impair reintegration into society. We aimed to clarify whether brain volume reduction occurs during the acute phase of sepsis in patients with acute brain damage. In this prospective, noninterventional observational study, brain volume reduction was evaluated by comparing head computed tomography findings at admission with those obtained during hospitalization. We examined the association between brain volume reduction and performance of the activities of daily living in 85 consecutive patients (mean age, 77 ± 12.7 years) with sepsis or septic shock. The bicaudate ratio increased in 38/58 (65.5%) patients, Evans index increased in 35/58 (60.3%) patients, and brain volume by volumetry decreased in 46/58 (79.3%) patients from the first to the second measurement, with significant increases in the bicaudate ratio (P< 0.0001) and Evans index (P= 0.0005) and a significant decrease in the brain volume by volumetry (P< 0.0001). The change rate for brain volume by volumetry was significantly correlated with the Katz index (ρ = −0.3790,P= 0.0094). In the acute phase of sepsis in this sample of older patients, 60–79% of patients showed decreased brain volumes. This was associated with a decreased capacity for performing activities of daily living.