BACKGROUND Proliferative inflammatory atrophy (PIA) has been proposed as a potential precursor for prostate cancer. The precise molecular abnormalities in prostatic atrophy compared to high-grade prostatic intraepithelial neoplasia (HGPIN) and carcinoma have not been fully defined. METHODS We utilized laser capture microdissection and microarray analysis to characterize cells of PIA, HGPIN, invasive prostatic carcinoma, and non-atrophic benign prostatic epithelium (NABE). Cytoglobin was selected for immunohistochemistry (IHC) validation. IHC stains were evaluated for proportion of positive glands, and intensity of cytoglobin staining. An immunoreactive score (IR score) was determined as the product of the percentage of positive staining and intensity. RESULTS Microarray analysis revealed probe sets that separated the microdissected cell types. Several genes showed overlapping expression patterns between PIA and PIN, and HGPIN and invasive carcinoma. Cytoglobin protein expression was detected in 57/93 (61%) of NABE and BPH cases, 92/93 atrophy (99%), 3/34 (9%) of PIN, and 23/61 carcinoma (37%) samples. The highest IHC scores were calculated for atrophy foci. A subset (33%) of atrophy cases showed the same low-cytoglobin expression level as PIN and carcinoma. CONCLUSIONS Prostatic epithelium can be stratified into normal, atrophic, PIN, and invasive carcinoma categories based on differential genetic signatures. Cytoglobin, a protein that can be induced in response to oxidative stress, was elevated in most atrophy foci, suggesting hypoxic, and/or oxidative damage. The lower level of cytoglobin seen in neoplastic cells and 33% of atrophy foci may indicate a shared susceptibility to oxidative damage for this subset of atrophy cases and prostatic neoplasia.