Objectives: This 52-week, double-blind, randomized, Phase 3 study evaluated the long-term safety of esmirtazapine 1.5 mg and 3.0 mg in elderly outpatients (aged ≥65 years) with insomnia. Methods: Participants were randomized to receive esmirtazapine 1.5 mg or 3.0 mg administered once nightly. Safety and tolerability (primary objectives) were assessed via adverse event (AE) reporting, routine clinical measurements [vital signs; electrocardiogram (ECG); laboratory parameters], and residual-effects assessments. Total sleep time (TST), wake time after sleep onset (WASO), and sleep latency (SL) were assessed (secondary objectives). Results: Of 259 randomized participants, 153 completed treatment. AEs and serious AEs were reported by 89.8% and 7.0%, respectively, of 1.5 mg recipients, and 88.5% and 3.8%, respectively, of 3.0 mg recipients. Discontinuations due to AEs were reported in 16.4% and 18.3% of participants receiving esmirtazapine 1.5 mg and 3.0 mg, respectively. The most frequent AEs (>10%) were nasopharyngitis, somnolence, dizziness, headache, dry mouth, weight increase, and fatigue. One participant died; the death was judged unrelated to treatment. Elevated eosinophil counts were noted, but not considered clinically significant. No remarkable or clinically relevant changes in laboratory parameters, vital signs, or ECG were observed. There was no evidence of residual effects; alertness at awakening increased by a median of 17 (1.5 mg) and 15 (3.0 mg) points from baseline, respectively, and ability to work/function by 12 points (both groups; all p<0.0001). Improvements from baseline in TST, WASO, and SL were observed. Conclusions Esmirtazapine was reasonably tolerated in elderly outpatients with insomnia. No significant safety signals were observed.