Antibiotic-loaded bone cement (ALBC) is commonly used in joint replacement therapy for prevention and treatment of bone infection and mechanical properties of the cement is still an important issue.The effects of ciprofloxacin and vancomycin was investigated on mechanical characterization of PMMA bone cement. Different properties of cement containing (0, 2.5, 5 and 10% W/W) antibiotics, including compressive and bending properties, microstructural, porosity and density were evaluated. Both antibiotics significantly reduced the density values and mechanical properties (compressive and flexural strength and modulus) in all groups in comparison to control over first two weeks (p < 0.05). This reduction was due to increased porosity upon antibiotic addition (3.05 and 3.67% for ciprofloxacin and vancomycin, respectively) in comparison to control (2.08%) (p < 0.001) and exposure to aqueous medium. Vancomycin as antibiotic with higher molecular weight (MW = 1485) had significant effect on compressive strength reduction of the cement at high amount compared to ciprofloxacin (MW = 367) (P < 0.01), there was no difference between two antibiotics at lower concentrations (P > 0.05). The effect of antibiotic loading is both molecular weight and drug content dependent. The time is also an important parameter and the second week is the probably optimum time to study mechanical behavior of ALBC.