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Phenol-soluble modulins (PSMs) are important <i>S. aureus</i> virulence factors that cause cytolysis, mast cell degranulation, and stimulate inflammatory responses. In this study, PSM production by <i>S. aureus</i> clinical isolates was measured by liquid chromatography/mass spectrometry (LC-MS) and correlated with staphylococcal protein A (<i>spa</i>) type and staphylococcal cassette chromosome <i>mec</i> (SCC<i>mec</i>) type. Of 106 <i>S. aureus</i> clinical isolates, 50 (47.2%) corresponded to methicillin-susceptible <i>S. aureus</i> (MSSA) and 56 (52.8%) to methicillin-resistant <i>S. aureus</i> (MRSA). LC-MS analysis revealed no significant difference in average PSMα3, PSMα4, PSMβ2, and δ-toxin production between MSSA and MRSA isolates, but PSMα1, PSMα2, and PSMβ1 production were higher in MSSA than MRSA. This study demonstrated that average PSMα1–α4, PSMβ1–β2, and δ-toxin production by SCC<i>mec</i> type II strains was significantly lower than the IV, IVA, and V strains. Most of the SCC<i>mec</i> type II strains (<i>n</i> = 17/25; 68.0%) did not produce δ-toxin, suggesting a dysfunctional Agr system. The <i>spa</i> type t111 (except one strain) and t2460 (except one strain producing PSM α1–α4) did not produce PSMα1–α4 and δ-toxin, while average PSM production was higher among the t126 and t1784 strains. This study showed that the genotype of <i>S. aureus</i>, specifically the <i>spa</i> and SCC<i>mec</i> types, is important in characterizing the production of PSMs.