By immunohistochemistry, lactoferrin (Lf) expression was retrospectively investigated in 40 formalin-fixed paraffin-embedded kidney samples, obtained at surgery from an equal number of patients. Histologically, 28 cases were clear cell carcinomas (CCC), 7 papillary carcinomas (PC) and 5 chromophobe carcinomas (CC). Ten specimens of unaffected renal parenchyma were utilized as tissue control. On 4-microm thick sections, the Lf immunoreactivity was revealed either by a rabbit polyclonal or mouse monoclonal anti-human Lf antisera; the quantification of Lf immunoreactivity was performed using an intensity-distribution (ID) score. A positive immunoreaction by both anti-Lf antibodies was found in 62.5% (25/40) of RCC, mainly evident and diffuse by monoclonal antiserum. The immunoreactivity was observed in the cytoplasmic boundary of neoplastic cells in CCC and PC, while in CC Lf showed a diffuse granular cytoplasmic localization. Moreover, significant differences in Lf ID score were found among CCC and non-CCC variants (P<0.00001), the former showed a lower score; no relationships between immunohistochemical data and the sex or age of patients, grade of RCC, stage of the disease or degree of terminal anemia were encountered. Normal unaffected tubular structures were positive for Lf; glomeruli were unstained. The reduced Lf immunoexpression in some CCC may be because of the down-regulation of Lf gene due to the frequent deletion of 3p regions reported in this RCC variant.