Structural　image-guided　near-infrared　spectral　tomography　(NIRST)　has　been　developed　as　a　way　to　use　diffuse　NIR　spectroscopy　within　the　context　of　image-guided　quantification　of　tissue　spectral　features.　A　direct　regularization　imaging　(DRI)　method　for　NIRST　has　the　value　of　not　requiring　any　image　segmentation.　Here,　we　present　a　comprehensive　investigational　study　to　analyze　the　impact　of　the　weighting　function　implied　when　weighting　the　recovery　of　optical　coefficients　in　DRI　based　NIRST.　This　was　done　using　simulations,　phantom　and　clinical　patient　exam　data.　Simulations　where　the　true　object　is　known　indicate　that　changes　to　this　weighting　function　can　vary　the　contrast　by　10%,　the　contrast　to　noise　ratio　by　20%　and　the　full　width　half　maximum　(FWHM)　by　30%.　The　results　from　phantoms　and　human　images　show　that　a　linear　inverse　distance　weighting　function　appears　optimal,　and　that　incorporation　of　this　function　can　generally　improve　the　recovered　total　hemoglobin　contrast　of　the　tumor　to　the　normal　surrounding　tissue　by　more　than　15%　in　human　cases.　(C)　2018　Optical　Society　of　America　under　the　terms　of　the　OSA　Open　Access　Publishing　Agreement.