Objective: To explore the effect of chronic hypoxia on the proliferation and dedifferentiation of LLC-PK1 cells. Methods: The cells were either exposed to hypoxia(3%O2) or maintained in normoxia(18%O2) followed by the assessment of ［3H］-thymidine incorporation and cell number as indices of cellular proliferation and sodium-dependent transport of glucose and a minoisobutyric acid(AIB) as indices of differentiation. The activity of protein kinase C(PKC) was determined with radionuclear technique. Results: Exposure of quiescent cultures to hypoxia for 16 h resulted in a significant increase in ［3H］-thymidine followed by a significant increase in cell number at 24 h in comparison with respective normoxic controls. Confluent cultures exposed to 72 h of hypoxia exhibited significant inhibition of α-methyl glucose and AIB uptakes when compared with their respective normoxic counterparts. Hypoxia also activated PKC at 4 h followed by a subsequent return to baseline with reactivation at 24 h which remained sustained up to 72 h, suggesting a biphasic acute and sustained activation of PKC. Furthermore, the hypoxia-induced alterations in ［3H］-thymidine incorporation as well as α-methyl glucose and AIB transport activities were mitigated by inhibitors of PKC. Conclusion: Chronic hypoxia induces both proliferation and dedifferentiation of LLC-PK1 cells mediated, in part, by the sustained activation of PKC.