Cholera toxin-induced intestinal secretion in intact rats requires a functioning myenteric plexus. The aim of this investigation was to determine whether neural elements were essential for cholera toxin to produce a secretory effect in human isolated ileum. Mucosal preparations were mounted in Ussing chambers. Cholera toxin was applied apically and short-circuit current monitored for 3 hr, at which point forskolin was given. Cholera toxin (10 microg/ml) induced a tetrodotoxin-insensitive increase in short-circuit current in muscle-stripped preparations of human ileum. The increase was not additive with the action of forskolin (25 microM). Cholera toxin exerts a marked nonneural secretory effect in human ileal mucosa in vitro, probably by the same mechanism as forskolin, namely elevation of cyclic AMP.