Luminal additions of normal short-chain fatty acids (SCFA: 3-6 carbons) increased transmural potential difference (PD: lumen negative) across rat everted colon in a dose-dependent manner. 2. The PD response to SCFA adapted rapidly and was not evoked by further cumulative addition of the same acid (self-adaptation) or different acids (cross-adaptation). 3. A broad range of SCFA derivatives were tested as potential stimulators of the PD response and cross-adaptation with propionate: a single carboxyl group and 3-6 carbon-chain were an absolute requirement for recognition. 4. These results suggest that SCFA-reception mechanism of the rat colonic mucosa has some sort of chemical specificity for stimulating electrogenic secretory response.