Manufacturing processes in the semiconductor and pharmaceutical industries often produce alcohol mixture byproducts. Therefore, the esterification of alcohol mixtures may be an important step in reusing wastes from these industries. There are two alternative methods for using the alcohol mixtures as feed for reactive distillation (RD). The first method separates this mixture into pure alcohols first and then follows with esterification using the RD column. The second method uses direct esterification of the alcohol mixture in a RD column, and then separates the mixed-ester products. This paper discusses the esterification of a n-butanol (BuOH) and n-amyl alcohol (AmOH) mixture with acetic acid (HAc). This study presents two important results based on optimizing the total annual cost (TAC). First, the mixed BuOH/AmOH system, with direct esterification with RD followed by product separation, is more economical than the system that first separates the mixture. Second, this study proposes a novel economical indirect-sequence design flowsheet with aqueous reflux. Another important issue in this study is the choice of the relative feed location, because the boiling point of acid lies between that of the two alcohols (i.e., BuOH < HAc < AmOH). Reaction kinetics is an important factor to be considered in determining the feed location of the alcohol mixture.