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Health-related quality of life (HRQOL) is often reduced with glaucoma, but associated factors are poorly understood.To determine factors associated with reduced HRQOL in medically and surgically treated patients with glaucoma.Prospective cohort study at a tertiary referral glaucoma practice, with 160 consecutive, prospectively enrolled medically or surgically treated adult patients with glaucoma.All patients completed 2 HRQOL questionnaires (the 25-item National Eye Institute Visual Function Questionnaire and the Adult Strabismus–20 questionnaire [AS-20]). Thirty-six patients had undergone glaucoma drainage device surgery, 51 underwent trabeculectomy, and 73 were medically treated. Factors considered for association with HRQOL in multiple regression analyses were age, sex, best-eye and worst-eye mean deviation on Humphrey visual fields, treatment modality, best-eye and worst-eye visual acuity, and diplopia.The mean (SD) age of participants was 69 (13) years, 63% were female, 97% were white, 93% were not Hispanic, and the mean deviation (SD) was −13 (10) dB. Reduced HRQOL was associated with worse diplopia (Diplopia Questionnaire score) on 6 subscales (range of partial r2 [rp2], 0.207-0.069). Reduced HRQOL was associated with lower best-eye mean deviation on 5 of 6 subscales (rp2 range, 0.379-0.027), lower worst-eye mean deviation on 4 of 6 (rp2 range, 0.242-0.046), treatment group on 3 of 6 (rp2 range, 0.190-0.025), lower worst-eye visual acuity on 5 of 6 (rp2 range, 0.063-0.025), lower best-eye visual acuity on 2 of 6 (rp2 range, 0.032-0.017), and younger age on 2 of 6 (rp2 range, 0.021-0.014). In adjusted analyses, glaucoma drainage device was associated with worse HRQOL in 3 AS-20 subscales compared with trabeculectomy and 2 AS-20 subscales compared with medical. Differences ranged from −14.7 to −7.4, with half the absolute magnitude of the full range of the 95% CI ranging from 9.2 to 5.7.Our findings support the assertion that reduced HRQOL is common in surgically and medically treated patients with glaucoma. Overall, poor HRQOL in patients with glaucoma is moderately associated with worse diplopia, lower mean deviation on visual field testing in either eye, poorer visual acuity in either eye, treatment type, and younger age. Previous glaucoma drainage device surgery was specifically associated with poorer HRQOL compared with trabeculectomy or medical treatment. Psychosocial effects of glaucoma drainage device should be considered when counseling patients with glaucoma.