His tenure as president of the PRI in Mexico City ended abruptly when evidence emerged that he had organized a prostitution ring operating out of the party's offices, using public funds to pay women recruited through intermediaries for his personal use. A labor court settlement with three women dismissed for refusing his sexual demands provided documented confirmation of at least part of the conduct. The case languished for years due to what prosecutors would later characterize as grave omissions by earlier investigators, and was only reopened in 2020.

Operating in Chicago during the 1893 World's Fair, Holmes constructed a hotel specifically designed to trap and kill victims — a building fitted with gas lines, sealed rooms, and a basement crematorium. His case is notable for the industrial quality of the enterprise: the fraud, the manipulation of accomplices, and the systematic disposal of evidence. The precise number of his victims remains unknown, in part because his own confessions were contradictory and self-serving.