The aim of this study was to evaluate the effect of intralesional tamoxifen on keloids, particularly on the concentration of fibroblasts, dermal inflammatory infiltrate, and collagen degeneration. A prospective study was carried out to evaluate keloids in 13 patients of both genders pre- and post-treatment with intralesional tamoxifen. Two samples of keloid lesions were obtained by 4-mm punch biopsies during the study: the first at the time of diagnostic confirmation of keloid and the other eight weeks later at the end of intralesional tamoxifen treatment. The biopsy samples were placed in 10% buffered formalin for HE staining and morphological and morphometric study. The degree of collagen fiber reduction and inflammatory infiltration were analyzed. Student’s t-test was used for statistical analysis of the mean number of fibroblasts before and following tamoxifen treatment ( P < 0.05). The degree of collagen fiber reduction and inflammatory infiltration were absent before treatment and present in 100% of cases after treatment, while the mean number of fibroblasts was significantly lower after intralesional tamoxifen treatment ( P < 0.0001). We conclude that intralesional administration of tamoxifen promoted an inflammatory stimulus and collagen fiber reduction as well as a significant reduction in the number of fibroblasts that produce collagen. Impact statement Effective treatment of keloid that is a commonly recurrent dermatosis is very difficult, even after standard treatment. Standard treatment consists of partial resection of the lesion (shaving excision), in addition to local corticosteroid injection. Therefore, there is interest in alternative forms of topical treatment, e.g., selective estrogen receptor modulators, particularly tamoxifen has demonstrated in vitro studies to be a promising drug. Nevertheless, there is scarcity of publications on the effects of intralesional tamoxifen on keloids have been found, leading us to the conception of the present study. In this study, tamoxifen has proven to be an interesting alternative drug for the topical treatment of keloid, allowing us to conclude that the intralesional application of tamoxifen in keloids promotes a variable but ever-present inflammatory stimulus, associated with intense reduction of collagen fiber, in addition to a significant decrease in the number of fibroblasts that produce collagen and are involved in disease maintenance.