As was shown in our previous work, the intracellular pH (pH i ) of cultured human fibroblasts depends on cell density. The pH i is low in single cells, higher in cells, forming small groups and maximal in a sparse monolayer. On the other hand, the pH i is low in areas of confluent monolayers. In the present work, we show that the effects of inhibitors of various pH-controlling mechanisms as well as inhibitors of key enzymes in signal transduction pathways depend on the local cell density. We have found that N-ethylmaleimide and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole, known as inhibitors of V-type H + ATPase, inhibit the elevation of pH i induced by cell-cell contact interactions; meanwhile Cd 2 + ions, which inhibit H + conductive pathway, cause an increase of pH i in a confluent monolayer. Our data revealed also that the Na + /H + antiporter does not play an essential role in the pH i regulation by intercellular contacts.Inhibitors of phospholipase A 2 (4-bromophenacyl-bromide), phospholipase C (neomycin) and protein kinase C (H-7) dramatically change the way the pH i is modulated by local cell density. It is suggested that cell-cell interactions regulate cell activities via modulation of pH i , which is under positive control from phospholipase A2 and under negative control from protein kinase C.