Isotopic labeling (deuteration) is known to affect the phase behavior of polystyrene (PS) and poly(methyl methacrylate) (PMMA) blends, but little is known regarding the changes in the interfacial properties at the PS/PMMA interface due to deuteration of PS and/or PMMA. To investigate these potential changes, secondary ion mass spectrometry (SIMS) Was used to measure real-space depth profiles of dPS in hPS:dPS/hPMMA bilayers, with the hPS:dPS blend being well within the single-phase region of the phase diagram. Profound changes in the thermodynamic behavior of this system at the polymer/polymer interface are observed in the form of significant segregation of dPS to the hPS:dPS/hPMMA interface. The observation of a depletion hole during the formation of an equilibrium excess of dPS implies that the energetic gain at the interface per dPS chain has to be > kT. These results cannot be described, even qualitatively, using previously reported charigges in chi for PS/PMMA due to isotopic labeling. The previously reported values of X for dPS/hPMMA and hPS/hPMMA actually predict a depletion of dPS at the hPS:dPS/hPMMA interface rather than the observed segregation. The observed interfacial excess is quantified by generating theoretical profiles, using self-consistent mean-field theory (SCMF), and fitting an effective interaction energy parameter Delta chi(p), as a function of temperature. This parameter represents the asymmetry in dPS/hPMMA and hPS/PMMA interactions. The temperature dependency of Delta chi(p), was found to be a factor of 3-4 greater than any of those reported for chi of PS/PMMA. It was also found that SCMF theory accurately describes the concentration dependency of dPS segregation at a constant dPS molecular weight using a coticentration-independent Delta chi(p); however, Delta chi(p) was found to be dependent oil dPS molecular weight.