OBJECTIVES: To estimate the relationship between the maximum possible financial impact (MPFI) of a new medicine on the United Kingdom (UK) National Health Service (NHS) and the probability of the drug being recommended for use in England and Wales by the National Institute for Health and Clinical Excellence (NICE). METHODS: Data were abstracted from the NICE guidance document and costing template for decisions made about drugs between January 2001 and March 2011. MPFI was calculated by multiplying the population eligible for treatment with the new drug based on the UK marketing indication by the upper bound estimate for the annual cost of treatment. Descriptive, logistic, and recursive partitioning decision analyses were used to estimate the relationship between the MPFI of a new medicine and the probability of recommendation for use with or without restrictions. Multivariable analyses controlled for other clinical and economic variables that have been shown to be correlated with the probability of recommendation for use, including the cost per quality-adjusted life-year (QALY) gained. RESULTS: In all analyses, MPFI was an important predictor of the recommendation for use, in addition to cost per QALY. In the univariate analysis, the mean MPFI was £140 million for medicines not recommended and £92 million and £31 million for those recommended with and without restrictions, respectively. In the logistic analysis, the coefficient on the MPFI variable was statistically significant. In the recursive partitioning decision analysis, the second split of the data for classifying recommendations, after cost per QALY, was for submissions with an MPFI above or below £130 million. CONCLUSIONS: In England and Wales, besides cost-effectiveness ratio, MPFI on the NHS may be an important determinant of whether a new drug is recommended for use with or without restrictions.