Structural abnormalities of the perineurium from six spontaneously diabetic dogs (diabetes duration 4-8 years and six control animals were quantified using detailed electron microscopic morphometric methods on superficial peroneal nerve biopsy specimens. Total perineurial sheath thickness (microm) was significantly increased in diabetic (8.8+/-0.6) compared to control animals (6.2+/-0.3) (P < 0.02). This was attributed to a significant increase in the mean perineurial lamellar width in diabetic (0.49+/-0.03) compared to control (0.40+/-0.01) (P < 0.04) animals. The number of lamellae also showed a non-significant increase in diabetic animals (7.8+/-0.4) compared to controls (6.9+/-0.13) (P < 0.06). There was no change in the mean interlamellar space in diabetic (0.7+/-0.05) compared to control (0.6+/-0.06) (P = 0.15) animals. The total interlamellar space was increased in diabetic (5.7+/-0.5) compared to control (4.1+/-0.36) (P < 0.04) animals. The perineurial cell basement membrane thickness (nm) was significantly increased in diabetic (126.9+/-9.8) compared to control (62.8+/-6.1) (P < 0.005) animals. The current study has demonstrated significant abnormalities of the perineurium in the spontaneously diabetic dog, which may have relevance to the pathogenesis of diabetic neuropathy.