A series of rhodanine-3-acetic acid derivatives were synthesized and investigated for their antibacterial activity against gram-positive bacteria including multidrug-resistant clinical isolates. Among these compounds, 6k with a MIC of 2 lg/mL was as active as the standard drug (norfloxacin) but less active than oxacillin against S. aureus. The compounds 6b, 6e, 6h, 6k, 6n, and 6u presented better activities against multidrug-resistant Staphylococcus aureus than the standard drugs (norfloxacin and oxacillin), especially 6k with a MIC of 1 lg/mL. However, none of the compounds were active against gram-negative bacteria at 64 lg/mL.