Endoneurial macrophages are crucially involved in the pathogenesis of neuropathies. Historically, the macrophage response in neuropathies is believed to be of hematogenous origin. However, recent studies could demonstrate an intrinsic generation of the early macrophage response by resident endoneurial macrophages after traumatic nerve injury and in a model of hereditary neuropathy. We hypothesized that the local macrophage response might suffice to generate an appropriate macrophage response in mild neuropathies, supplemented by infiltrating macrophages only in severe nerve pathology. To clarify this assumption, we investigated the macrophage response in acrylamide‐induced neuropathy as a model of a slowly progressive neuropathy with a defined onset. We induced the neuropathy in bone marrow chimeric mice carrying green fluorescent protein transgenic bone marrow, allowing the differentiation of resident (GFP⁻) and invading hematogenous endoneurial (GFP⁺) macrophages. Quantification of GFP⁻ and GFP⁺ endoneurial macrophages in the sciatic nerve revealed an increase only of resident macrophages in proximal parts, whereas in distal parts a minor additional influx of hematogenous macrophages was observed. The immunohistochemical profile of GFP⁻ and GFP⁺ macrophages was similar but distal GFP⁻ macrophages were differentially activated than their GFP⁺ counterparts. Characterization of CCR2‐deficient mice revealed a function for this chemokine system in attracting hematogenous macrophages but not in generating the intrinsic macrophage response. In conclusion, we provide evidence for a role of resident macrophages in acrylamide‐induced neuropathy. Resident endoneurial macrophages intrinsically generate the macrophage response in this slowly progressive neuropathy, which only becomes supplemented by hematogenous macrophages in distal areas of more pronounced damage. © 2008 Wiley‐Liss, Inc.