Background MAGEL2 is one of several genes typically inactivated in the developmental obesity disorder Prader-Willi syndrome (PWS). The physiological consequences of loss of MAGEL2, but without the concurrent loss of other PWS genes, are not well understood. Gene-targeted mutation of Magel2 in mice disrupts circadian rhythm and metabolism causing reduced total activity, reduced weight gain before weaning, and increased adiposity after weaning. Principal Findings We now show that loss of Magel2 in mice causes reduced fertility in both males and females through extended breeding intervals and early reproductive decline and termination. Female Magel2-null mice display extended and irregular estrous cycles, while males show decreased testosterone levels, and reduced olfactory preference for female odors. Conclusions Our results suggest that loss of MAGEL2 contributes to the reproductive deficits seen in people with PWS, and further highlights the role of normal circadian rhythm in the maintenance of fertility.