DNA-dependent protein kinase, the catalytic subunit associated with the Ku heterodimer (Ku70/Ku86), has been implicated in switch recombination. Therefore, we tested whether certain stimuli known to promote switch recombination may act in part by inducing Ku expression. We find that resting B cells contain relatively low levels of nuclear Ku, but that Ku expression can be up-regulated by culturing the cells with two switch stimuli. First, IL-4 and CD40 engagement in combination, but neither of these stimuli acting alone, strongly induce Ku expression; Ku levels rise within 24 h, about 2 days before switch recombination is detected. Second, dextran-conjugated anti-IgD Abs strongly induce Ku expression, which is variably enhanced by IL-5, but not by IL-4. Our data suggest that switch recombination may be regulated, at least in part, through changes in the nuclear expression of Ku.