Many patients with Parkinson's disease (PD) suffer from sialorrhea. Sialorrhea is often treated with anticholinergics and botulinum toxin, but some adverse effects have limited the use of these treatments. Dihydroergotoxine mesylate is an α-adrenergic blocking agents as well as some affinities to the dopaminergic and serotonin (5-HT) receptors. In the current study, we examine the safety and efficacy of dihydroergotoxine mesylate in PD patients. This study consisted of 2 phases. The intervention was 2.5-mg oral dihydroergotoxine mesylate twice daily in both phases. The first phase is a three-week open-label single-arm trial (n = 10). The second phase was a six-week randomized controlled trials with a crossover design (n = 20). Efficacy was assessed using the United Parkinson's Disease Rating Scale (UPDRS) sialorrhrea subscore and Sialorrhea Clinical Scale for PD (SCS-PD). In the first phase, the UPDRS sialorrhea score was 3.5 ± 0.53 vs. 1.9 ± 0.57 prior to and after the treatment (P = 0.004). The SCS-PD score decreased from 15.8 ± 2.78 to 9.9 ± 3.00 after the treatment (P = 0.005). The response rate (defined by at least 30% reduction in SCS-PD score) was 60%. In the second phase of crossover trial, the UPDRS sialorrhea score was 3.00 ± 0.56 in placebo weeks vs. 2.00 ± 0.65 on dihydroergotoxine in dihydroergotoxine weeks (P = 0.001). The SCS-PD was 12.50 ± 2.84 and 9.25 ± 2.86 versus, respectively (P < 0.001). The response rate was 10% and 55%, respectively (P = 0.003). There were no significant adverse effects. Dihydroergotoxine mesylate is safe and effective for sialorrhea in PD patients.