Background: Aerobic exercise is a promising add-on treatment to counteract structural and functional impairments of the hippocampal formation and associated clinical outcome in schizophrenia. However, current evidence regarding exercise effects on the hippocampal formation in patients with schizophrenia is still limited and inconclusive. Therefore, we aim to assess the impact of aerobic exercise on the volume and connectivity of the hippocampal formation and explore the clinical relevance of potential exercise-induced adaptations.Methods: In this multicenter randomized-controlled clinical trial, a total of 92 patients with schizophrenia (31 female, 61 male) underwent serial MRIs and were randomly assigned to either an aerobic exercise intervention or a flexibility, strengthening and balance training as a control group. Both groups exercised three times per week for six months. Clinical assessments and structural and functional MRI scans were conducted at three consecutive timepoints. Linear mixed models, linear and logistic regressions and mediation analyses were computed to examine the effects of exercise on the volume and connectivity of the hippocampal formation and their potential clinical relevance.Results: In the aerobic exercise group, but not in the control group, volumes within the hippocampal formation increased, especially in the cornu ammonis. No effects of exercise on hippocampal formation connectivity were observed.Conclusions: The present study supports the evidence in favor of beneficial effects of aerobic exercise on hippocampal volume in patients with schizophrenia with most robust effects on CA3 and therefore underlines the potential of aerobic exercise to prevent neurodegenerative processes in this key region involved in memory processes.