We studied the association between bisphosphonate use and risk of gastrointestinal (GI) cancers in a nationwide retrospective cohort from Denmark. All users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) were used as the exposed group, with three age- and gender-matched controls from the general population (n = 310,683) as the nonexposed group. The main outcome was occurrence of cancer of the esophagus, ventricle, small intestine, colon, pancreas, gallbladder or bile duct, or liver. Except for colon cancer, most of the GI cancers were rare. For clodronate and raloxifene, no excess risk was present for any of the GI cancers. For alendronate, an excess risk of esophageal and liver cancer was observed; however, the excess risk was most pronounced at low doses and short duration of observation. No dose-response relationship was present except for colon cancer with alendronate, where a decrease was seen with increasing dose so that at high doses a seemingly protective effect was present (≥1 defined daily dose, HR = 0.29, 95% CI 0.14-0.62). For etidronate, an excess risk of esophageal, liver, pancreas, and gallbladder and bile duct cancers was seen. Again, no relationship with dose or duration of observation was present. An excess risk of esophageal and liver cancers may be seen with alendronate and etidronate. However, the association may not be causal as no dose-response or time relationship was present. For colon cancer, the decline with increasing alendronate dose may be due to a "healthy user" effect.