Mean diffusivity (MD), the rotationally invariant magnitude of water diffusion that is greater in cerebrospinal fluid (CSF) and smaller in organized brain tissue, has been suggested to reflect schizophrenia-associated cortical atrophy. Regional changes, associations with CSF, and the effects of genetic predisposition towards schizophrenia, however, remain uncertain. Six-direction diffusion tensor imaging DTI and high-resolution structural images were obtained from 26 schizophrenia patients, 36 unaffected first-degree patient relatives, 20 control subjects and 32 control relatives (N=114). Registration procedures aligned diffusion tensor imaging (DTI) data across imaging modalities. MD was averaged within lobar regions and the cingulate and superior temporal gyri. CSF volume and MD were highly correlated. Significant bilateral temporal, and superior temporal MD increases were observed in schizophrenia compared with unrelated control probands. First-degree relatives of schizophrenia probands showed larger MD measures compared with controls within bilateral superior temporal regions with CSF volume correction. Superior temporal lobe brain tissue deficits and proximal CSF enlargements are widely documented in schizophrenia. Larger MD indices in patients and their relatives may thus reflect similar pathophysiological mechanisms. However, persistence of regional MD effects after controlling for CSF volume, suggests that MD is a sensitive biological marker of disease and genetic liability, characterizing at least partially distinct aspects of brain structural integrity.