Using small palindromes to monitor meiotic double-strand-break-repair (DSBr) events, we demonstrate that two distinct classes of crossovers occur during meiosis in wild-type yeast. We found that crossovers accompanying 5:3 segregation of a palindrome show no conventional (i.e., positive) interference, while crossovers with 6:2 or normal 4:4 segregation for the same palindrome, in the same cross, do manifest interference. Our observations support the concept of a ''non''-interference class and an interference class of meiotic double-strand-break-repair events, each with its own rules for mismatch repair of heteroduplexes. We further show that deletion of MSH4 reduces crossover tetrads with 6:2 or normal 4:4 segregation more than it does those with 5:3 segregation, consistent with Msh4p specifically promoting formation of crossovers in the interference class. Additionally, we present evidence that an ndj1 mutation causes a shift of noncrossovers to crossovers specifically within the ''non''-interference class of DSBr events. We use these and other data in support of a model in which meiotic recombination occurs in two phases-one specializing in homolog pairing, the other in disjunction-and each producing both noncrossovers and crossovers. I N yeast, deletion of the meiosis-specific gene MSH4, which, despite its name, is said to have no involvement in mismatch repair (Ross-Macdonald and Roeder 1994), usually leaves residual crossovers, and these crossovers have reduced interference (Novak et al. 2001). In Caenorhabditis elegans, however, which is characterized by strong crossover interference as well as by cis-acting ''pairing centers'' that promote synapsis of homologous chromosomes (Dernburg et al. 1998;MacQueen et al. 2005;Phillips and Dernburg 2006), deletion of him-14, a homolog of MSH4, eliminates essentially all crossing over while apparently leaving intact the ability to repair meiotic double-strand breaks (Zalevsky et al. 1999). On the basis of these data, Zalevsky et al. (1999) suggested that yeast, and other creatures lacking pairing centers, have two kinds of crossing over, one of which is Msh4 independent, has little or no crossover interference, and serves to establish effective pairing of homologous chromosomes. Stahl et al. (2004) noted that the concept of two kinds of crossing over provides an explanation for the apparent correlation between the strength of interference and the fraction of crossovers that are Msh4 dependent in a given interval. Furthermore, Malkova et al. (2004), using a statistical analysis, which in the light of information presented here appears oversimplified, reported that the distribution of crossovers along the left arm of chromosome VII in wild-type yeast was better described by a two-kinds-of-crossover model than by the simple ''counting model'' for interference (Foss et al. 1993). More compelling support came from the phenotype of mms4 and mus81 deletions. Each of these mutations caused a reduction in crossing over but not in interference, while deletion of MMS4 a...