Background In view of the serious health risks and high costs to the health-care system of misuse and abuse of overthe-counter (OTC) analgesics, this article describes a rationale and prototype for new safety or compliance packaging for OTC drug products that are sold in pill form (e.g., tablets, caplets and gelcaps) inside blister packs. The proposed packaging is not simply promoting the use of blister packs for pills; that utility is already well known. It is an integrated system in which blister packs of pills can, themselves, be packaged, labeled and sold, offering a dosedirected unit-of-use design with enhanced warnings and directions to help prevent consumers from taking more than the instructed dose of pill-form medicines. Method Literature and information searches were conducted in publicly available databases and websites to (1) assess safety problems (serious adverse events and fatalities) associated with OTC analgesics and (2) determine public perceptions and knowledge about their use. Results Each year in the US, there are an estimated 100,000 hospitalizations and 16,500 deaths due to NSAID overdosing, and 26,000 hospitalizations and 1,600 acute liver failure cases due to acetaminophen poisoning. Many adults take more than the recommended dose and in some cases use multiple products containing acetaminophen and ibuprofen. Risk factors, such as alcohol use or pre-existing liver disease, exacerbate problems associated with acetaminophen misuse and abuse. In pediatric cases, dosing errors are often related to confusion over different product formulations, dosing strengths, and the use of inappropriate dosing devices. Consumers are often unaware of the active ingredients in, and correct doses of, drugs they are taking; they underestimate the risks associated with misuse of OTC medicines, and they frequently discard the packaging on which the drug's directions, warnings and dosing instructions are located. Conclusion Optimal compliance packaging should (1) keep the instructions, warnings and dosing directions attached to the blister card of pills at all times, thus avoiding the problem of cartons and package inserts being thrown away once the package is opened; (2) increase the surface area of the packaging, without adding bulk, to provide space for the use of larger font sizes and enhanced directions and warnings that are more conspicuous, explicit and memorable; (3) organize the pills into logical, unit-of-use (per-dose maximum and perday maximum) sets or rows; (4) limit the number of pills in a unit-of-use package to coincide with the instructed maximum dose and maximum days of use for a specific product.