This study evaluated the combined effects of thermocycling and compressive load-cycling on microleakage of computer-aided design/computer-assisted manufacture molar crowns. Sixteen ceramic (Vita Mark-II) and 16 composite resin (Paradigm MZ-100) crowns were milled using the CEREC 3D system. Eight crowns of each group were cemented to prepared molars using Panavia F 2.0, and 8 were cemented using RelyX Unicem Clicker. Specimens were thermocycled for 500 cycles and subjected to load-cycling for 1,000,000 cycles (60 to 600 N). Specimens were then tested for microleakage. Data were analyzed statistically using the Tukey post hoc test. All composite resin crowns survived load and thermal fatigue, while 6 ceramic crowns developed cracks. There were no statistically significant differences among groups regarding microleakage scores. Paradigm MZ-100 crowns were more crack-resistant to combined load and thermal fatigue than those composed to Vita Mark-II. However, microleakage scores of both types of crowns were similar.