Simple Summary Calcium electroporation is a new cancer therapy wherein a high, rapid influx of calcium, facilitated by electrical pulses, is used to kill cancer cells. This pilot study aimed to evaluate the safety and feasibility of this new treatment for patients with non-curable esophageal cancer. The treatment was administrated during an endoscopic examination, under general anesthesia, and in an outpatient setting. Eight patients were treated. One severe adverse event occurred (requiring a single blood transfusion) and another three mild side effects were seen. Two patients reported dysphagia relief after treatment and one patient had a partial response evaluated by CT. Six months after treatment, the same patient was still in good condition, without the need for further treatment. Calcium electroporation was conducted in eight patients with only a few side effects. More studies are warranted to evaluate clinical efficacy. Calcium electroporation (CaEP) is a novel cancer therapy wherein high intracellular calcium levels, facilitated by reversible electroporation, trigger tumor necrosis. This study aimed to establish safety with CaEP within esophageal cancer. Patients with non-curable esophageal cancer were included at Copenhagen University Hospital Rigshospitalet in 2021 and 2022. In an outpatient setting, calcium gluconate was injected intratumorally followed by reversible electroporation applied with an endoscopic electrode. The primary endpoint was the prevalence of adverse events, followed by palliation of dysphagia. All patients were evaluated with CT and upper endoscopies up to two months after treatment. The trial was registered at ClinicalTrials.gov (NCT04958044). Eight patients were treated. One serious adverse event (anemia, requiring a single blood transfusion) and three adverse events (mild retrosternal pain (two) and oral thrush (one)) were registered. Initially, six patients suffered from dysphagia: two reported dysphagia relief and four reported no change. From the imaging evaluation, one patient had a partial response, three patients had no response, and four patients had progression. Six months after treatment, the patient who responded well was still in good condition and without the need for further oncological treatment. CaEP was conducted in eight patients with only a few side effects. This study opens the way for larger studies evaluating tumor regression and symptom palliation.