To determine whether systemic replacement with combined esterified estrogen (EE) and methyltestosterone (MT) (EE + MT) would reduce symptoms and promote clinical improvement in postmenopausal women with dry eye syndrome (DES). Retrospective, noncomparative, interventional case series. Investigators reviewed the charts of 11 postmenopausal women treated within the last 3 years with EE + MT. The mean patient age was 65.2 years (standard deviation [SD] 11.4, range 48–84 years). The mean treatment duration was 12.2 months (SD 6.2 months, range 4–24 months). Ten (91%) of 11 patients reported improvement in dry eye symptoms while receiving treatment. For these 10, relief occurred after an average of 4.1 months of treatment (SD 3.2, range, 1–9 months). Treatment with EE + MT may be efficacious for DES of various etiologies. A randomized placebo-controlled trial is planned to further evaluate these encouraging findings.