Acquired strabismus fixus is a rare form of severe esotropia described most frequently in patients with high axial myopia and infrequently associated with other conditions. Refractive errors, cataracts, and ocular motility disorders are common in patients with trisomy 21. We report two unusual cases of patients with trisomy 21 who developed severe acquired restrictive strabismus fixus. Both patients were successfully treated with medial rectus recession followed by lateral rectus and superior rectus myopexy combined with additional medial rectus weakening, including free tenotomy in one case.