This paper describes the progressive effects of severe copper depletion on pancreatic weight, structure, amylase content and responses to secretin and caerulein, as well as a number of general body parameters (appearance, body weight and blood indices). Copper depletion was produced by feeding young rats a copper-deficient diet alone or together with either of the two chelating agents D-penicillamine or triethylene tetramine (Trien). After 6 weeks, the copper-deficient diet alone had relatively little effect on general body parameters but reduced gland weight and the secretory response to caerulein. Addition of D-penicillamine ductal and islet tissue relatively intact; gland weight was markedly reduced, and gland amylase was reduced virtually to zero; and the secretory response to caerulein was almost abolished while that to secretin was reduced. The effects of Trien on general body parameters were less severe; the secretory response to secretin was also less affected, while acinar cell atrophy, gland amylase and the secretory response to caerulein were affected to the same extent as with D-penicillamine. The effects of severe copper depletion on the pancreas were largely irreversible after 13 weeks on a copper-supplemented diet.