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<i>Staphylococcus aureus</i> is a commensal skin bacterium and a causative agent of infectious diseases. Biofilm formation in <i>S. aureus</i> is a mechanism that facilitates the emergence of resistant strains. This study proposes a mechanism for the regulation of biofilm formation in <i>S</i>. <i>aureus</i> through strain-specific physiological changes induced by the plant steroid diosgenin. A comparison of diosgenin-induced changes in the expression of regulatory genes associated with physiological changes revealed the intracellular regulatory mechanisms involved in biofilm formation. Diosgenin reduced biofilm formation in <i>S</i>. <i>aureus</i> ATCC 6538 and methicillin-resistant <i>S</i>. <i>aureus</i> (MRSA) CCARM 3090 by 39% and 61%, respectively. Conversely, it increased biofilm formation in <i>S</i>. <i>aureus</i> ATCC 29213 and MRSA CCARM 3820 by 186% and 582%, respectively. Cell surface hydrophobicity and extracellular protein and carbohydrate contents changed in a strain-specific manner in response to biofilm formation. An assessment of the changes in gene expression associated with biofilm formation revealed that diosgenin treatment decreased the expression of <i>icaA</i> and <i>spa</i> and increased the expression of <i>RNAIII</i>, <i>agrA</i>, <i>sarA</i>, and <i>sigB</i> in <i>S</i>. <i>aureus</i> ATCC 6538 and MRSA CCARM 3090; however, contrasting gene expression changes were noted in <i>S</i>. <i>aureus</i> ATCC 29213 and MRSA CCARM 3820. These results suggest that a regulatory mechanism of biofilm formation is that activated <i>sigB</i> expression sequentially increases the expression of <i>sarA</i>, <i>agrA</i>, and <i>RNAIII</i>. This increased <i>RNAIII</i> expression decreases the expression of <i>spa</i>, a surface-associated adhesion factor. An additional regulatory mechanism of biofilm formation is that activated <i>sigB</i> expression decreases the expression of an unknown regulator that increases the expression of <i>icaA</i>. This in turn decreases the expression of <i>icaA</i>, which decreases the synthesis of polysaccharide intercellular adhesins and ultimately inhibits biofilm formation. By assessing strain-specific contrasting regulatory signals induced by diosgenin in <i>S</i>. <i>aureus</i> without gene mutation, this study elucidated the signal transduction mechanisms that regulate biofilm formation based on physiological and gene expression changes.