This chapter recounts the disappearance of many nameless guests at Holmes's World's Fair Hotel. Descriptive details include odd smells of gas, cleaner, and medicine running rampant throughout the hotel. Larson sheds light on Holmes's killing practices: using his vault or chloroform to subdue and snuff out his victims. Holmes then disposes of the bodies by burning the body in his kiln, dissolving of pieces and parts in pits of quicklime, or having the flesh scrapped to make ready for selling the skeleton.
Larson uses this chapter to develop Holmes's character, opening the door further to the chambers of the killer's mind as the murders appear to increase in frequency. For example, Holmes prefers being near when death overtakes his victims rather than killing face to face. He enjoys hearing the faint sounds of struggle coming from his vault as his subjects are approaching their last breaths. Holmes varies his patterns of slayings and body disposal methods to avert suspicion — a possible explanation for Holmes's activities going unnoticed for so long.
The title of the chapter, "Modus Operandi," essentially implies that killing random guests at the hotel has become standard operating procedure for Holmes.