OBJECTIVE: The Comparative Effectiveness Index (CEI) provides a quantitative method of transforming efficacy data into effectiveness indices. In lieu of head-to-head randomized controlled trials, the CEI uses efficacy, adherence, and safety data to facilitate the drug evaluation process by providing a single value index for each therapeutic alternative. METHODS: Efficacy data from clinical trials serve as surrogate markers of effectiveness. In analyzing two hypothetical anti-hypertensive drugs, A and B, the efficacy of each drug is ranked on a nominal scale based on the literature: A=10 and B=8. The drug with the highest nominal value is the most efficacious. However, this value needs to be moderated by adherence and safety data. Adherence rates, calculated from claims databases for example, are: A=60% and B=90%. The formula for calculating the Modified Efficacy Score (MES) of each drug is the (adherence rate*efficacy score)/100: A=6 and B=7.2. Adverse events (AE) reported in the clinical trials are ranked based on severity, the scale is anchored at 0 and 100 where 0=No AE and 100=Death. Each AE is assigned a value depending on its severity then multiplied by the probability of its incidence. This is repeated for each AE and summed. The inverse of the sum, the Adverse Events Score (AES), is used in the final computation so that both MES and AES modifiers have a direct relationship with the CEI. The AES for the drugs are: A=3.33 and B=5.00. The MES is multiplied by the AES to calculate the CEI. Consequently, the CEI would be: A=19.98 and B=36.00. Although drug A was more efficacious, drug B is more effective. CONCLUSION: The CEI provides healthcare decision-makers with valuable comparisons between therapeutic alternatives, but it requires further development and validation. Incorporating measures of dispersion for efficacy and compliance in a sensitivity analysis can generate more comprehensive indices.