OBJECTIVE Fatigue after aneurysmal subarachnoid hemorrhage (aSAH) is common and usually long-lasting, and it has a considerable negative impact on health-related quality of life (HRQOL), social functioning, and the ability to return to work (RTW). No effective treatment exists. The dopaminergic regulator (-)-OSU6162 has shown promising results regarding the mitigation of fatigue in various neurological diseases, and therefore the authors aimed to investigate the efficacy of (-)-OSU6162 in alleviating fatigue and other sequelae after aSAH. METHODS A double-blind, randomized, placebo-controlled, single-center trial was performed in which 96 participants with post-aSAH fatigue were administered 30-60 mg/day of (-)-OSU6162 or placebo over a period of 12 weeks. Efficacy was assessed using the Fatigue Severity Scale (FSS), the Mental Fatigue Scale (MFS), the Beck Anxiety Inventory (BAI), the Beck Depression Inventory II (BDI-II), the SF-36 questionnaire, and a neuropsychological test battery. Assessments were performed at baseline, after 1, 4, 8, and 12 weeks of treatment, and at follow-up, 8 weeks after treatment. RESULTS The 96 participants with post-aSAH fatigue were randomized to treatment with (-)- OSU6162 (n = 49) or placebo (n = 47). The FSS, MFS, and BDI scores improved significantly in both groups after 12 weeks of treatment, whereas the BAI scores improved in the placebo group only. HRQOL improved significantly in the SF-36 domain "Vitality" in both groups. Neuropsychological test performances were within the normal range at baseline and not affected by treatment. The FSS score was distinctly improved in patients with complete RTW upon treatment with (-)-OSU6162. Concomitant use of antidepressants improved the efficacy of (-)- OSU6162 on the FSS score at week 1 beyond the placebo response, and correspondingly the use of beta- or calcium-channel blockers improved the (-)-OSU6162 efficacy beyond the placebo response in MFS scores at week 4 of treatment. There was a significant correlation between improvement in FSS, BAI, and BDI scores and the plasma concentration of (-)-OSU6162 at the dose of 60 mg/day. No serious adverse events were attributable to the treatment, but dizziness was reported more often in the (-)-OSU6162 group. CONCLUSIONS Fatigue and other sequelae after aSAH were similarly alleviated by treatment with (-)-OSU6162 and placebo. (-)-OSU6162 improved fatigue, as measured with the FSS score, significantly in patients with complete RTW. There seemed to be synergetic effects of (-)-OSU6162 and medications interfering with dopaminergic pathways that should be explored further. The strong placebo response may be exploited in developing nonpharmacological treatment programs for post-aSAH fatigue.