Purpose: To describe the involvement of the lacrimal gland (LG) in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES).Design: Observational, cross-sectional study. Participants: Twenty-one patients with BPES (10 female, 11 male) aged on average 15 years (range, 2e39 years), from 3 Brazilian medical centers and 1 Portuguese medical center.Methods: Patients had their ocular surface evaluated with slit-lamp biomicroscopy, and tear production quantified with the Schirmer test I. The LG volumes were measured on computed tomography (CT) scans in the BPES sample and in a group of age-matched subjects imaged for nonorbital diseases. Sixteen patients were screened for mutations in the FOXL2 gene.Main Outcome Measures: Lacrimal meniscus height, Schirmer test I, presence of superficial punctate keratopathy (SPK), LG volume, and molecular analysis of the FOXL2 gene.Results: Absence of LG was detected bilaterally in 9 patients (42.8%) and unilaterally in 2 patients (9.5%). When considering only patients with measurable LG, the median volume was 0.22 cm 3 in the right eye (range, 0.06e0.36 cm 3 ) and 0.24 cm 3 in the left eye (range, 0.08e0.34 cm 3 ). These values were significantly lower than those for the age-matched controls (median ¼ 0.54 right eye and 0.53 left eye; P < 0.05). There was a significant association between deficiency of tear production and LG volume reduction and agenesis. Molecular analysis of the FOXL2 gene revealed the presence of 8 distinct mutations, 4 of them novel ones. A significant reduction of LG size or agenesis was associated with mutations affecting protein size (due to underlying changes in the stop codon location) or the DNA-binding forkhead domain (Fisher exact test, P ¼ 0.021). In 3 probands, the underlying genetic defect was not found.Conclusions: This is the first study reporting LG volumes in BPES, describing a significant number of patients with LG agenesis. The association between alacrima and BPES is not incidental, and a thorough evaluation of tear production is recommended especially if ptosis surgery is planned. Ophthalmology 2017;124:399-406 ª