The poxvirus molluscum contagiosum (MC) has a worldwide distribution and its prevalence is on the rise. Here we report that the MCV MC013L protein inhibits glucocorticoid and vitamin D, but not retinoid or estrogen, nuclear receptor transactivation. A direct interaction of MC013L with glucocorticoid and vitamin D receptor is supported by yeast two-hybrid, GST pull-down, and far Western blot analyses. Glucocorticoids act as potent inhibitors of keratinocyte proliferation, while vitamin D and retinoids promote and block terminal differentiation, respectively. Therefore, MC013L may promote efficient virus replication by blocking the differentiation of infected keratinocytes. MC013L may be the first member of a new class of poxvirus proteins that directly modulate nuclear receptor-mediated transcription.