The purpose of this study was to investigate and compare microleakage of prefabricated posterior NuSmile® ZR and EZCrowns when cemented with BioCem and Ketac Cem dental cements.Forty extracted permanent teeth (n equals 10 per group) were fitted for either NuSmile or EZCrowns prefabricated posterior zirconia crowns and cemented with BioCem or Ketac Cem, for a total of four groups. Crowned teeth were placed in Dulbecco's Phosphate Buffered Saline solution at 37 degrees Celsius for 24 hours. Teeth were thermocycled between five degrees Celsius and 55 degrees Celsius for 6,000 cycles, stained with two percent basic fuchsin, sectioned, and visually inspected for microleakage utilizing stereomicroscopy on a four-point scale. Data were statistically analyzed using one-way analysis of variance, SNK (P<.05).All samples in this study had microleakage. NuSmile® ZR crowns demonstrated significantly less microleakage when cemented with BioCem and compared to Ketac Cem (P=.002). NuSmile® ZR cemented with BioCem had significantly less microleakage compared to EZ-Crowns with Ketac Cem (P=.002).In this in vitro investigation, BioCem cement had significantly less microleakage in zirconia pre-fabricated crowns compared to Ketac Cem, and NuSmile® ZR crowns cemented with BioCem resulted in significantly less microleakage than EZ-Crowns cemented with Ketac Cem.