Pancreatoscopy-guided electrohydraulic lithotripsy (EHL) has shown potential in the treatment of patients with obstructive chronic calcifying pancreatitis (CCP). We aimed to prospectively investigate the efficacy and safety of EHL as first-line therapy in patients with CCP of the pancreatic duct (PD). A prospective single-center consecutive case series was performed including symptomatic CCP patients with obstructing stones >5mm in the head or neck of the pancreas. Stone fragmentation was performed using EHL. Primary study outcome was technical success. Secondary outcomes were clinical success, adverse events, and number of interventions. Thirty-four consecutive patients were included. Complete or partial stone clearance after EHL was achieved in 24 patients (70.6%). Pancreatoscopy was not performed because of failure to cannulate the PD (n= 5) or resolution of stones after stent placement at the index endoscopic retrograde pancreaticography (ERP) procedure (n= 3). After successful PD cannulation, pancreatoscopy was technically successful in 24 of 26 patients (92.3%). In 1 patient, the stone could not be visualized because of a resilient stricture. Complete stone clearance was achieved in 20 patients (80%) and partial clearance in 5 patients (20%), after a median of 2 ERP procedures (interquartile range, 2) and 1 EHL procedure (interquartile range, 1). In patients who underwent pancreatoscopy with EHL, mean Izbicki pain score at baseline was 62.3 ± 23.1 (25/25) and dropped significantly to 27.5 ± 35.0 (22/25) at the 6-month follow-up (P< .001). The most common adverse event was acute pancreatitis, all mild and treated conservatively (n= 7). Pancreatoscopy-guided EHL is a promising treatment for symptomatic CCP patients with obstructive PD stones. (Clinical trial registration number: NTR6853.).