We examine oil-specific asphaltene inhibitor chemistry of two chemically distinct asphaltene inhibitors. Laboratory and field tests show oil-specific asphaltene inhibitor performance for two geographically distinct crude oils. The crude oils and their corresponding asphaltenes were characterized by total acid number (TAN), elemental analysis, Fourier transform infrared spectroscopy (FTIR), and electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS). ESI FT-ICR MS reveals differences in the relative abundance of heteroatom-containing compound classes in the two crude oils and the two asphaltenes. We identify acidic and/or basic species that may be responsible for the observed differences in inhibitor chemistry. Asphaltene inhibitor specificity can be explained by acid-base-type interactions between the inhibitor and polar species in the crude oils or asphaltene fractions. ESI FT-ICR MS provides the first evidence for inhibitor effectiveness related to heteroatom content derived from detailed polar chemical composition.