The hypothesis that the accumulation of endoneurial edema can exert forces sufficient to occlude transperineurial vessels was tested using light microscopy and computer-assisted morphometry in rat sciatic nerve. Experimental nerves were exposed to a concentration of 10% procaine HCl, which from previous studies has been demonstrated to routinely produce an edematous neuropathy. For each vessel, a “constriction ratio” was defined by dividing its minimum intraperineurial lumen area by the average for minimum endoneurial and epineurial lumen cross-sectional areas. Constriction ratios were 0.91 ± 0.26 (mean ± SD) for control vessels and 0.28 ± 0.25 for vessels in the procaine group (p < 0.005). In addition, a strong negative correlation was observed between the morphologic demonstration of nerve edema and the transperineurial vessel constriction ratio (r = −0.85; p < 0.002). It is concluded that in neuropathies characterized by widespread edema and increased endoneurial fluid pressures, the concomitant constriction of transperineurial vessels could diminish nerve blood flow and facilitate nerve injury.