Antibacterial activity of 20 acetophenone derivatives was evaluated against two Gram-positive and three Gram-negative organisms, namely, Bacillus subtilis NCIM 2718, Staphylococcus aureus NCIM5021, Salmonella typhi NCIM2501, Enterobacter aerogenes NCIM5139, and Proteus vulgaris NCIM2813 by two-fold dilution method. The most active amongst this group of compounds were 4-methyl, 2-hydroxy, 3-bromo, 4-ethoxy, 3-nitro and 4-nitro acetophenones. Quantitative structure-activity relationships were developed by dividing the data into training and validation sets, the former was used to develop and the latter was used to test the models. Spatial, electronic and topological descriptors were predominantly found to influence the activity. The statistical measures such as r2 (0.76-0.91), cross-validated r2 (0.56-0.85), F-ratio and predicted residual sum of square values were found to be in the acceptable range. The developed models were able to predict the activity of the validation data set within the 99% confidence limit (except for two data points). 4-Nitroacetophenone was found to be the most slimicidal in nature. Bacterial Adhesion to Hydrocarbons (BATH) assay indicated that Staphylococcus aureus NCIM5021 had the most hydrophobic cell surface of these five organisms. Cell surface hydrophobicity of organisms also had an impact on the antibacterial activity of the acetophenones. © 2008 The Authors.