Thiocyanate (SCN) inhibits H+ secretion and increases the resistance and potential difference (PD) of the gastric mucosa. These results support our separate-site electrogenic theory of HCl secretion. Recent work shows that an ATP-driven mechanism in the gastric mucosa can produce H+ by a neutral exchange of K+ for H+. The SCN increase in resistance and PD, if due to an inhibition of a high-conductance mechanism(s) in the secretory plasma membrane, is not easily compatible with the neutral mechanism. Therefore, the possibility was examined that SCN induces the increase in resistance by other mechanisms. The HCl and NaCl concentration profiles in the pit and tubular lumina were calculated. The effects of SCN were determined with isotonic, hypotonic, hypertonic, buffered, and high [H+] secretory solutions. The results indicate that SCN produces an increase in resistance of about 130 omega. cm2 of the plasma membranes of the tubular cells. A scheme is proposed that incorporates the neutral K+-H+ mechanism into an electrogenic system.