Naphthenic acids (NA) are a complex mixture of carboxylic acids that are natural constituents of oil sand found in north-eastern Alberta, Canada. NA are released and concentrated in the alkaline water used in the extraction of bitumen from oil sand sediment. NA have been identified as the principal toxic components of oil sands process-affected water (OSPW), and microbial degradation of lower molecular weight (MW) NA decreases the toxicity of NA mixtures in OSPW. Analysis by proton nuclear magnetic resonance spectroscopy indicated that larger, more cyclic NA contain greater carboxylic acid content, thereby decreasing their hydrophobicity and acute toxicity in comparison to lower MW NA. The relationship between the acute toxicity of NA and hydrophobicity suggests that narcosis is the probable mode of acute toxic action. The applicability of a (quantitative) structure-activity relationship [(Q)SAR] model to accurately predict the toxicity of NA-like surrogates was investigated. The U.S. Environmental Protection Agency (EPA) ECOSAR model predicted the toxicity of NA-like surrogates with acceptable accuracy in comparison to observed toxicity values from Vibrio fischeri and Daphnia magna assays, indicating that the model has potential to serve as a prioritization tool for identifying NA structures likely to produce an increased toxicity. Investigating NA of equal MW, the ECOSAR model predicted increased toxic potency for NA containing fewer carbon rings. Furthermore, NA structures with a linear grouping of carbon rings had a greater predicted toxic potency than structures containing carbon rings in a clustered grouping.