Spastic esophageal motility disorders constitute a wide spectrum of distinct disorders. Distal esophageal spasm (DES), which is aberrantly used as diffuse esophageal spasm, is one such disorder [1]. The first classification of esophageal motility disorders was designed by Spechler and Castell in 2001 based on manometry metrics. This classification differentiated disorders with known etiologies, such as scleroderma and achalasia, from other disorders without investigated pathophysiological basis, which were further subdivided into three subclasses: hypercontractile, hypo-contractile, and discoordinated disorders [2]. This classification has gradually evolved into the Chicago classification for esophageal motility disorders, which requires interpreting high-resolution manometry (HRM) [3]. DES is an uncommon motility disorder with a reported prevalence of 3–9% among symptomatic patients [4], a patient mean age of approximately 60 years, and a slight female predominance [5]. Unfortunately, an effective treatment has still not been introduced. This might be due to the lack of clinical trials and the different pathophysiological aspects of the disease [6]. Three therapy methods have been utilized so far: 1. pharmacologic treatments with nitrates [7], phosphodiesterase inhibitors (PDI) [8], calcium channel blockers (CCB) [9], tricyclic antidepressants (TCAs) [10], and proton pump inhibitors (PPI) [11]; 2. endoscopic therapy with peroral endoscopic myotomy (POEM) [12], Botox injection [12], and endoscopic esophageal dilation [7]; and 3. surgical intervention [13]. The purpose of this study is to compare the efficacy of two common medications, diltiazem and fluoxetine, in the treatment of DES among patients referred to the esophageal motility disorder ward at Taleghani hospital, a tertiary referral center in Tehran, Iran. The routine usage of these drugs is not currently recommended due to a lack of data concerning their efficacy.