Objective: Autism is the fastest growing neurodevelopmental disability for which there is no cure. Defects in synaptic formation underlie macrocephaly, commonly found in autism. Previously we demonstrated high levels of synaptic, anabolic, secreted Amyloid Precursor Protein alpha (sAPP) in autism plasma and brain tissue. Objective: To determine if males with autism and high sAPPα show large brain volumes. Method: Brain MRI volumetric analysis from 4 autistic boys (7–12 yrs) with elevated plasma sAPPα, compared to 6 age matched neurotypical boys. T1 weighted, axial 1.5 Tesla MRI scans were transferred to FMRIB Software library (FSL) volumetric software. Derived brain volumes were segmented into gray matter volume (GMV), white matter (WMV), cerebral spinal fluid (CSFV), and total intracranial volume (TIV). Analysis was done by “weighted pairs” according to age. Percent differences in GMV, WMV, CSFV, TIV, and OFC were computed between autistic vs. neurotypical subjects and then results weighted so each age had equal total weight. Due to small sample size, we employed bootstrap analysis to calculate 95% bias corrected and accelerated confidence intervals. Results: No overlap between bootstrapped estimated confidence intervals and 0 in GM, WM, CSFV, and TIV. This supports the anabolic hypothesis, e.g., “cellular” intracranial volume (GMV and WMV) is significantly greater in autistic vs. neurotypical subjects, and corresponding “non-cellular” space (CSFV) is reduced. OFC difference overlapped 0, suggesting at least partial compensation between losses in CSFV vs. gains in GMV and WMV. No differences in IQ or Childhood Autism Rating Scale, but qualitative differences in Autism Diagnostic Interview-Revised scores were seen between autistic boys. Conclusion: Brain volume is enlarged for autistic boys with high levels of sAPP, consistent with sAPP driven anabolic pathway and macrocephaly.