An increased prevalence of macrocephaly defined by occipital-frontal circumference (OFC) is a consistent finding in autism. Several possible mechanisms have been proposed, the most compelling being early brain overgrowth. However, the proportion of non-neural tissues (NNT) that contribute to OFC has not been reported. Using quantitative magnetic resonance imaging (MRI) methods we analyzed the relationships between OFC and total brain (TBV), ventricular, surface cerebrospinal fluid (CSF)/meningeal, and NNT volumes in subjects with autism. Sixty male subjects (34 autistic; 26 controls) seven years of age and older were used in this study. Compared to other measures, NNT volume was most significantly related to OFC (r values > 0.8, p<or=0.001), though NNT volume did not differ between the groups. Ventricular volume was also uniformly related to OFC (r approximately 0.3, p> 0.06). In contrast, the OFC-TBV relationship was less robust in those with autism (r=0.25, p<or=0.09) and only significant in the controls (r=0.58, p<or=0.001). Conversely, subjects with autism had a more robust and significantly different relationship between subarachnoid CSF/meningeal volume than controls (r=0.53 and 0.24; p<or=0.001 and 0.12, respectively). Possible explanations for these findings are discussed in the context of potential OFC differences that may occur in accelerated early brain growth associated with autism.