In this work, we report the first detailed theoretical comparative conformational investigation between two different classes of hydrofluoropolyethers: dihydro-and dimethoxyfluoropolyethers.The main objective was to determine a cost-effective computational methodology that could accurately reproduce the energetic rankings and thermal weight factors of the simplest examples of those two classes calculated with M08-HX/triple-f//M08-HX/double-f benchmark model chemistries. Between the tested methodologies, M08-HX/aug-pcseg-2//M08-HX/pcseg-1 was found to be the most appropriate, exhibiting a good accuracy and considerable reduction in computational cost with respect to the benchmark, being more than three times faster than M08-HX/aug-pcseg-2//M08-HX/aug-pcseg-1. This cost-effective approach will be essential in future work when studying larger hydrofluoropolyethers, where the computational complexity associated with increasing number of conformers will require such approximations. K E Y W O R D S atmospheric chemistry, conformational sampling, density functional theory, hydrofluoropolyethers, model chemistry Int J Quantum Chem. 2017;117:e25381.