OBJECTIVE To explore the phenotypes and genotypes of Staphylococcus aureus (S. aureus) hetero-resistant to erythromycin and clindamycin and compare their detection methods so as to report results accurately to guide clinical rational use of antibiotics. METHODS D test was used to detect the phenotypes of S. aureus hetero-resistant to erythromycin. And then the results of two methods (automated instrument and disk diffusion) were analyzed. All strains were continuously passaged for 50 generations to verify the phenotypic and genotypic stability of hetero-resistance. ErmA, ermC and msrA genes were amplified by multiplex polymerase chain reaction (PCR). RESULTS Among 95 erythromycin-sensitive strains, there were 70 strains hetero-resistant to erythromycin (73.7%). The primary 70 strains were all susceptive to erythromycin (MIC ≤ 0.25 µg/ml) and clindamycin (MIC ≤ 0.25 µg/ml) with the cards of GP-67 of VITEK2 Compact. With D tests, the results were difficult to observe. The passaged 70 strains were all resistant to erythromycin (MIC >8 µg/ml) and susceptible to clindamycin (MIC ≤ 0.25 µg/ml) and D test positive with the cards of GP-67 of VITEK2 Compact. The primary and 50(th) generation of herero-erythromycin resistant strains were stable in susceptibility test results. The primary and the 50(th)th generation strains were all ermA gene positive, ermC and msrA negative with PCR results. CONCLUSIONS The phenotypes and genotypes of hetreo-erythromycin resistant S. aureus strains were stable. Missed detection with VITEK2 Compact may affect the proper use of erythromycin and clindamycin. Laboratory technicians should identify the erythromycin-susceptible strains by disk diffusion method.