Intussusception (IS), an invagination of a portion of the intestine into itself, has recently attracted considerable interest after the withdrawal of a rotavirus vaccine because of reports on increased risk of IS shortly after vaccination. The present study was designed to shed further light on the mechanism of IS formation and its prevention. Intussusception was induced in adult mice by intraperitoneal injection of lipopolysaccharide (LPS; 8 mg/kg) from salmonella typhimurium. The presence of IS was confirmed at laparotomy. The serum levels TNF-α were measured with ELISA. Six hours after LPS injection, 14.5% of the animals demonstrated IS. A total of 65 animals received rofecoxib (20 mg/kg), a selective COX2 inhibitor, 15–30 min before intraperitoneal injection of LPS, and only two (3%) in this group demonstrated IS 6 h later (P < 0.05 vs. control). We confirmed the well-known increase in serum TNF-α levels in response to LPS; however, this increase was not blocked by rofecoxib pretreatment. Notably, there was no correlation between the serum TNF-α levels and the development of IS. The results show that the occurrence of IS can be significantly decreased by pretreatment with a selective COX-2 inhibitor.