The human Y chromosome is replete with amplicons-very large, nearly identical repeats-which render it susceptible to interstitial deletions that often cause spermatogenic failure. Here we describe a recurrent, 1.8-Mb deletion that removes half of the azoospermia factor c (AZFc) region, including 12 members of eight testis-specific gene families. We show that this "b2/b3" deletion arose at least four times in human history-likely on inverted variants of the AZFc region that we find exist as common polymorphisms. We observed the b2/b3 deletion primarily in one family of closely related Y chromosomes-branch N in the Y-chromosome genealogy-in which all chromosomes carried the deletion. This branch is known to be widely distributed in northern Eurasia, accounts for the majority of Y chromosomes in some populations, and appears to be several thousand years old. The population-genetic success of the b2/b3 deletion is surprising, (i) because it removes half of AZFc and (ii) because the gr/gr deletion, which removes a similar set of testis-specific genes, predisposes to spermatogenic failure. Our present findings suggest either that the b2/b3 deletion has at most a modest effect on fitness or that, within branch N, its effect has been counterbalanced by another genetic, possibly Y-linked, factor.