The Domino Hazard Index used in this work was previously introduced by Tugnoli, Khan, Amyotte, and Cozzani (2008a, 2008b) to assess domino effect hazards caused by a unit in a given layout. This index has been used to compare several layouts in order to select the one with lower risk. A set of piecewise differentiable equations have been developed to describe all graphical descriptions given in the original proposal. Then, this work introduces a complete formulation aimed to achieve optimal facility layouts taking into account the main variables affecting this index. The result of this formulation is a mixed-integer non-linear program (MINLP), which can be solved using a GAMS code. The result can provide substantial support for decision-makers during the design stage. (C) 2013 Elsevier Ltd. All rights reserved.