Particularly large acetaminophen overdoses, termed massive, create a therapeutic challenge given the standardized, N-acetylcysteine-based treatment. One consideration in addition to N-acetylcysteine is the initiation of hemodialysis due to the dialyzable nature of acetaminophen, though encumbered by the concurrent removal of the antidote, N-acetylcysteine. Such cases of large acetaminophen overdose, along with possible concomitant ingestions of other drugs or inactive ingredients, can be complicated by challenging-to-interpret clinical signs and laboratory findings. We describe a case of a 46-year-old man for whom we were consulted regarding consideration of dialysis treatment 7 hours after ingestion of 125 g of acetaminophen. The patient developed multiple early signs and laboratory findings consistent with a significant acetaminophen overdose. He also developed a rarely described, likely acetaminophen-interference-induced laboratory abnormality. Finally, he possibly had toxicity from an "inactive" ingredient. He was treated with a single session of prolonged hemodialysis (9.5 hours) and increased dosing of N-acetylcysteine with a positive outcome. Herein, we discuss the decision making and interpretation of clinical data pertaining to dialysis treatment and other therapies after a massive acetaminophen overdose.