Balance between damaging influences and repair mechanisms determines the degree of tissue deterioration by inflammatory and other injury processes. Destabilization of the proximal tubular barrier was previously shown to be induced by IFN, a cytokine crucial for linking innate and adaptive immune responses. EGF was implicated in rescue mechanisms from renal injury. To study the interplay between the two processes we determined if EGF can prevent IFN-induced barrier permeabilization. EGF did not counteract but even exacerbated IFN-induced decrease of transepithelial electrical resistance in LLC-PK1 monolayers. For this effect Erk1/2 activation was necessary linking barrier regulation to EGF-induced cell cycle progression. In contrast to its damage-intensifying effect, EGF also facilitated regeneration of epithelial barrier function after termination of IFN treatment. This effect was not mediated by Erk1/2 activation or cell proliferation since inhibition of these processes by U0126 did not prevent but ameliorated recovery. However, EGF accelerated the downregulation of caspase-3 in recovering cells. Similarly, a pan-caspase inhibitor was able to block caspase activity and, concomitantly, promote restoration of barrier function. Thus, barrier repair might be linked to an EGF-mediated anti-apoptotic mechanism. EGF appears to sensitize epithelial cells to the detrimental effects of cytokines but also helps to restore barrier function in the healing phase. The observed dual effect of EGF might be explained by the different impact of pro-proliferative and anti-apoptotic signaling pathways during and after IFN treatment. Timing of epithelial exposure to damaging agents and repair factors was identified as crucial parameter determining tissue fate.