In this study, the use of computer-aided molecular design (CAMD) is validated as a tool for enabling the discovery of new shrinkage-reducing compounds for possible use in portland cement composites and is framed as one of many multiscale modeling tools in a broad hierarchy of possibilities. Twelve additives were tested for their ability to inhibit shrinkage in Type I ordinary portland cement under both autogenous and drying conditions. The 12 additives included two commercial shrinkage-reducing admixtures (SRAs), two active ingredients of a commercial admixture [one of which was used to establish the quantitative structure–property relationships (QSPR)], two additional classified as potential SRA compounds based on the patent literature, four newly identified compounds predicted by using CAMD and an inverse quantitative structure–property relationship (I-QSPR), and two other compounds use to establish the QSPR relationship. The newly identified I-QSPR compounds were targeted for their ability to reduce the surface tension of water, a primary consideration for shrinkage-reducing activity. Results for both drying shrinkage and autogenous shrinkage indicate that the designed compounds perform similar to commercial admixtures, yet have different chemical functionalities. Hydration data and set measurements were also considered since selection of new SRAs is a multiparameter problem with many constraints. Thus, these newly identified shrinkage-reducing compounds can potentially provide additional options for use in portland cement concrete applications.