Objective: This was an analysis of the effect of pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response. Methods: For this analysis of CLARITY, a phase 2 study of adjunctive pimavanserin (N = 207) conducted between December 2016 and October 2018, sleep/wakefulness disturbances were measured with the 17-item Hamilton Depression Rating Scale (HDRS17) insomnia items (sum of items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline in HDRS17 insomnia factor score and KSS score, correlation between the HDRS17 insomnia factor score and KSS score, and change from baseline in the Sheehan Disability Scale (SDS) total score and Unproductive Days subscore in patients with a baseline KSS score ≥ 6. Results: At baseline, HDRS17 insomnia factor score ≥ 3 occurred in 76% of patients receiving placebo and 85% of patients receiving pimavanserin. The overall least squares (LS) mean weighted difference (SE) was −0.5 (0.32) with a 95% CI of −1.2 to 0.1 (P = .088) at week 5. Improvement was observed with pimavanserin versus placebo at weeks 2, 3, and 4, with effect sizes (ESs) of 0.370 to 0.524 (P < .05). For KSS score, the LS mean difference (SE) at week 5 was −1.1 (0.30) (95% CI, −1.7 to −0.5; P = .0003; ES = 0.627) for pimavanserin versus placebo. Among those with a KSS score ≥ 6 at baseline (n = 120 placebo and n = 42 pimavanserin), the LS mean difference (SE) in the mean SDS score at week 5 was −1.1 (0.46) (95% CI, −2.0 to −0.2; P = .019; ES = 0.442) for pimavanserin versus placebo. Conclusions: Adjunctive pimavanserin significantly improved sleep/wakefulness disturbance during treatment of MDD, an improvement that was associated with greater improvement in function.