To date, 1,4-naphthoquinone derivatives have not been reported as aromatase inhibitors. Based on the heme coordination mechanism, 2-amino-1,4-naphthoquinone compounds are considered to be a potential novel class of aromatase inhibitors because of the presence of heme coordinating atoms, i.e., amino N and carbonyl O atoms in their molecules. Recently, a series of 2-amino-3-chloro-1,4-naphthoquinones was reported to possess anticancer activity by our research group (Prachayasittikul et al., 2014). Herein, a set of eleven 2-amino(chloro)-3-chloro-1,4-naphthoquinone compounds (1-11, Figure 1(Fig. 1)) were investigated for their aromatase inhibitory activities, and the experimental activities of the compounds (1-11) were used for QSAR analysis. To elucidate the effects of structural modification on the core structure of 2,3-disubstituted-1,4-naphthoquinone, an additional set of 39 structurally modified compounds derived from compound series 1-11 (Figure 2(Fig. 2)) were constructed in silico, and their aromatase inhibitory activities were predicted using the constructed QSAR model.