We report 15 cases of a distinctive and previously unrecognized variant of high-grade prostatic intraepithelial neoplasia (HGPIN) that is characterized by polarization of enlarged secretory cell nuclei toward the glandular lumen. We designate this lesion inverted or hobnail HGPIN. In all cases inverted HGPIN was identified on needle biopsy where it merged with typical micropapillary-tufted HGPIN. Inverted secretory cell nuclei frequently demonstrated less prominent nucleoli than adjacent noninverted secretory cell nuclei, yielding a sense of maturation that falsely suggested a non-neoplastic process. Inverted HGPIN was associated with concurrent prostatic adenocarcinoma in seven cases and with atypical glands suspicious for carcinoma in two other cases, whereas in six other cases inverted HGPIN was the only lesion identified. In both radical prostatectomies that followed these biopsies that were available for review, inverted HGPIN was localized to the peripheral zone of the prostate where it merged with usual forms of HGPIN and carcinoma. Inverted HGPIN is a morphologically distinctive form of HGPIN that shares the association with carcinoma and peripheral zone localization with other recognized forms of HGPIN.