Cyclo-oxygenase (COX)-2 selective inhibitors (coxibs) were designed to reduce the incidence of gastrointestinal (GI) adverse events (AEs) which occur with non-selective NSAIDs (ns-NSAIDs). Etoricoxib and lumiracoxib are regarded as second generation coxibs because of their higher COX-2 selectivity. There are three published pooled analyses relating to the GI tolerability of etoricoxib (60-120mg/day) and lumiracoxib (200-400mg/day) which used individual patients data from studies sponsored by the manufacturers. We also reviewed new clinical trials published after the pooled analyses, to determine the global GI safety profiles of etoricoxib and lumiracoxib. We included discontinuations due to GI events, endoscopic ulcers, symptomatic ulcers, and ulcer complications. Current evidence suggests that etoricoxib and lumiracoxib have significantly more favorable GI profiles than ns-NSAIDs, and are similar to first generation coxibs with respect to GI safety. The most clinically important benefit of the coxibs is seen in the reduced rate of symptomatic ulcer and ulcer complications, which are still common in chronic NSAIDs users especially in high risk patients. In the largest GI outcome study of any coxib, TARGET, involving more than 18000 patients, lumiracoxib was associated with a 79% reduction in ulcer complications in patients not taking aspirin. The differences between etoricoxib or lumiracoxib and ns-NSAIDs in relation to ulcer complications are apparent early during treatment and remain constant over time during the course of treatment; therefore, benefit of etoricoxib and lumiracoxib can be seen in patients with high GI ulcer complication risk who require NSAIDs from the beginning of use to throughout the prescription duration.