Although the effect of NSAIDs such as celecoxib on the progression of colorectal polyps has been established, it is currently unknown how sufficiently high concentrations of celecoxib are reached in colonic tissue. Indeed, the lipophilic and poorly soluble celecoxib is orally dosed as an immediate release capsule without any colon-targeting delivery strategy. In the present study, we aimed to distinguish between plasma and gut driven caecal tissue accumulation of celecoxib in healthy volunteers. After developing a protocol to reliably collect colonic biopsies and contents, the disposition of celecoxib was assessed in plasma, caecal tissue and caecal contents collected after intake of a celecoxib capsule (200 mg; Celebrex®) with 240 mL of tap water. During a first colonoscopy (1.0-2.5 h after drug intake), plasma concentrations of celecoxib and its carboxy metabolite were increasing, while caecal tissue concentrations were relatively low. As no celecoxib was present in caecal contents, tissue accumulation was clearly plasma driven. During a second colonoscopy (6.0-7.5 h after drug intake), tissue concentrations of the drug and its metabolite were substantially higher despite decreasing plasma concentrations. As a high amount of celecoxib was found in the caecal contents, the increased tissue accumulation most likely resulted from direct uptake of celecoxib from the gut. These data demonstrate that incomplete small intestinal absorption of the poorly soluble drug celecoxib enables gut driven drug accumulation in caecal tissue, which is, most likely, critical for the role of this NSAID in the prevention of colorectal cancer.