A universal policy of prescribing PEP for people who have experienced any significant HIV risk exposure could never be cost–effective, even though at around £750 the cost of a month's triple combination therapy PEP for a single individual seems to compares extremely favourably with the likely lifetime costs of treating the same individual should he or she become infected with HIV. The cost–effectiveness of an intervention such as PEP can only be meaningfully calculated in terms of the amount of money that would need to be spent to prevent a single infection. On average, no more than about one out of every three hundred people who have a single episode of unprotected receptive anal sex with an HIV–positive person becomes infected as a result (Katz). So if all 300 came forward for PEP after their risk exposure, 299 would be treated 'unnecessarily', because they would not have become infected regardless of whether or not they received PEP. If doctors have to treat 300 people in order to prevent the one single infection, the cost of preventing that infection would be three hundred times £750, which makes £225,000. In blunt financial terms, this no longer compares so favourably with the lifetime costs of medical care.

The cost–effectiveness of PEP could be improved by using fewer or cheaper drugs; for example, if only two nucleoside analogue drugs were used (or if an additional protease inhibitor was reserved only for specific cases of the greatest risk) the cost per course of PEP would be approximately halved. Moreover, PEP would also be more cost–effective if it were delivered only to people whose circumstances meant that they were most at risk of becoming infected (effectively reducing the proportion of recipients who are being treated 'unnecessarily').

Possible criteria for prioritisation might include limiting PEP to cases in which people had a risk encounter with someone who was known for sure to be HIV–positive – even though the US guidelines for occupational use do not carry such a restriction. PEP would also become more cost–effective if offered only to people whose risk had been substantial, such as unprotected receptive anal or vaginal sex or shared drug injecting equipment. The first study based on public guidelines for non–occupational use of PEP includes receptive oral sex with ejaculation as sufficient grounds for treatment although in practice, few people came forwards for treatment solely on that basis, suggesting that individuals can self-select for treatment, balancing the risks of exposure against the risks and inconvenience of the drugs (Katz & Gerberding). Technology such as viral load testing of the HIV–positive partner might be employed, enabling the prioritisation of cases in which the HIV–positive partner had a high viral load, such as during advanced HIV infection, which might also be expected to increase the risk of transmission. Nevertheless, funding more than the occasional case of PEP for a sexual risk exposure is likely to be beyond the means of most genito–urinary clinic budgets.