BACKGROUND: Zinc oxide eugenol (ZOE) cement is a popular dental material due mainly to its analgesic, antibacterial and anti-inflammatory effects. The formulation of ZOE cement from nano particle-sized zinc oxide (ZnO) has the potential to increase these properties as well as reduce its adverse effects to the surrounding tissues. OBJECTIVE: This study evaluated the subcutaneous tissue response towards nano ZOE cements (ZOE-A and ZOE-B) in comparison to conventional ZOE (ZOE-K). METHODS: Test materials were implanted into 15 New Zealand white rabbits. Tissue samples were obtained after 7, 14, and 30 days (n = 5 per period) for histopathological evaluation of inflammatory cell infiltrate, fibrous tissue condensation, and abscess formation. RESULTS: ZOE-A showed the lowest score for the variable macrophage and lymphocyte at day 7. Both ZOE-A and ZOE-B presented lower fibrous tissue condensation and abscess formation compared to conventional ZOE-K. By day 30, ZOE-A exhibited less lymphocytic and neutrophilic infiltrate compared to the other materials, while ZOE-B had the lowest score for macrophages. ZOE-K exerted higher inflammatory cell response at almost all of the experimental periods. All of the materials resulted in thin fiber condensation after 30 days. CONCLUSIONS: Rabbit tissue implanted with ZOE-A and ZOE-B showed better response compared to ZOE-K.