Purpose:　The　relatively　poor　image　contrast　and　variation　in　the　neonatal　brain　size　are　technical　challenges　associated　with　the　typical　tract-based　spatial　statistics　(TBSS)　for　the　target　identification　and　normalization.　This　study　aimed　to　develop　a　rapid　and　reliable　pipeline　for　the　neonatal　TBSS.　Materials　and　methods:　A　rapid　TBSS　strategy　was　proposed　based　on　the　group-wise　target　choice　for　fractional　anisotropy　(FA)　derived　from　diffusion　tensor　imaging　(DTI).　The　most　representative　subject　of　the　entire　group　was　identified　via　(a)　initial　group-averaged　template　creation　(b)　followed　by　identification　of　the　target　with　the　minimum　warp　displacement　score　between　the　individual　and　the　group-averaged　template.　The　computation　time,　registration　quality,　measurement　of　regional　values,　and　statistical　analyses　were　evaluated　in　two　applications:　brain　white　matter　development　in　normal　term　neonates,　and　alterations　in　preterm　neonates　with　white　matter　lesions　compared　to　the　matched　controls.　These　performances　in　the　proposed　pipeline　were　compared　with　those　in　the　typical　and　previous　neonatal　TBSS　workflows.　Results:　Target　choice　using　the　proposed　strategy　is　faster,　compared　with　the　previous　TBSS　pipelines,　especially　with　the　increase　of　the　sample　size.　Registration　errors　between　individuals　and　the　target　are　assessed　through　warp　displacement　scores.　Smaller　warp　displacement　scores　are　observed　for　the　proposed　method　than　the　typical　pipeline.　Due　to　the　relatively　accurate　registration,　the　proposed　method　results　in　lower　standard　deviations　and　higher　averaged　values　of　FA　across　subjects.　Additionally,　more　areas　with　significant　changes　related　to　the　development　and　white　matter　lesions　are　detected　using　the　proposed　method　than　previous　TBSS　pipelines.　The　proposed　pipeline　provides　stronger　correlation　between　FA　and　gestational　age,　and　larger　difference　between　preterm　neonates　with　white　matter　lesions　and　controls.　Conclusion:　The　proposed　TBSS　pipeline　improves　the　efficiency　and　reliability　of　the　DTI　analysis　in　the　neonatal　brain.　(C)　2016　Elsevier　Inc.　All　rights　reserved.