Molecular-level characterization of petroleum asphaltenes is important for addressing reservoir concerns such as connectivity and flow assurance. Laser desorption single-photon ionization mass spectrometry (LDSPI-MS) has emerged as a favored technique for asphaltene analysis, because of its ability to detect these samples with minimal artifacts from fragmentation, aggregation, and multiple charging. However, questions persist regarding the sensitivity of LDSPI-MS to different components of asphaltenes, the molecular weight range detectable with the technique, and the importance of matrix effects. We present LDSPI-MS mass spectra of mixtures of model compounds and asphaltenes in various matrices to assess the significance of these effects. We observe that LDSPI-MS has comparable sensitivity for all studied model compounds and for asphaltenes, including compounds with molecular weight exceeding 1500 Da. In addition, only a minimal matrix effect is observed, as expected from considerations of the desorption and ionization mechanisms. The results add confidence to the previous conclusion of an LDSPI-MS study, in particular that (i) 1500 Da represents a maximum molecular weight for asphaltenes and (ii) the lack of fragmentation implies the dominance of island geometries in asphaltenes.