This study describes the infiltration and death of monocyte/macrophages and concomitant endoneurial expression of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) and neurotrophin receptor p75 (p75NTR) in the sciatic nerve at the early phases of experimental diabetic neuropathy induced in Lewis rats by streptozotocin (STZ) intraperitoneal injection. Immunocytochemistry and single nerve fiber immunostaining showed the presence of macrophages in diabetic nerves by weeks 2 and 3 after STZ administration, and the 15% of these cells were TUNEL positive. IL-1beta was evident in scattered macrophages, and along few isolated nerve fibers until week 5, when it became undetectable, in concomitance with complete endoneurial clearance of macrophages. p75NTR showed an up-regulation in the sciatic nerve of diabetic rats that began by week 3 after STZ administration, reached its peak by week 5, and returned then to a barely detectable level by week 6. These findings seem to indicate that macrophages and IL-1beta may be involved in the pathogenesis of diabetic neuropathy, participating not only to nerve damage but also to the promotion of an attempt of regeneration via p75NTR induction.