Molluscum contagiosum virus (MCV) is a human poxvirus that causes asymptomatic cutaneous neoplasms that can persist for months to years in the skin of healthy or immunodeficient individuals, particularly children. Infection with this virus is increasing and has become a troublesome complication for adults with AIDS. At present there is no specific preventive or treatment for the disease. All attempts to culture the virus have failed and little is known about it. The object of the project is to analyze the structure of the viral genome and determine its mode of expression and replication and identify potential therapeutic targets. The way in which the virus resists the human immune system is of particular interest. A set of overlapping plasmids containing all but the very ends of the MCV genome were sequenced by primer walking with an Applied Biosystems, model 373A automatic DNA sequencer. Taq polymerase cycle sequencing protocols with inosine triphosphate in place of guanosine triphosphate were used to avoid early termination of sequencing reactions and compression caused by the high (average 63.3%) GC content. The 190,289-base pair MCV sequence contained 588 open reading frames longer than 60 codons. Of these, we selected 163 as a conservative estimate of the gene complement. The proteins encoded by 104 predicted genes are homologous to proteins of other poxviruses and 59 are unique. Missing from MCV are 88 genes present in either vaccinia virus or variola virus. The missing genes include those responsible for nucleotide biosynthesis and modulation of the host response to infection. The new MCV genes include a chemokine homolog and a major histocompatability class I homolog that are predicted to have roles in MCV host defense.