We describe a family in which the largest hitherto reported pericentric inversion of chromosome 18, inv(18)(p11.22q23), segregates. Individuals heterozygous for the nonrecombinant inversion were unaffected. However, those heterozygous for either the dup(18p)/del(18q) or dup(18q)/del(18p) recombinant exhibited mild learning difficulty, personality disorders and deficient social behavior in the absence of mental retardation. Of the three family members tested, the behavioral abnormalities were more prominent in the two individuals with the dup(18p)/del(18q) recombinant than in the one with the dup(18q)/del(18p) recombinant. Genetic counseling issues for this family, in particular for the affected, include the enhanced probability of reduced fertility as well as the recurrence risk of the parental inversion equaling 1/2 in surviving offspring. This observation kindles the interest in determining the frequency of subtelomeric rearrangements in individuals with learning difficulty and deficiency in social interaction, phenotypic features often considered to be of multifactorial causation. © 2005 Nature Publishing Group All rights reserved.