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BACKGROUND AND AIMS 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). METHODS A prospective single center consecutive case series was performed including symptomatic CCP patients with obstructing stones of >5 mm 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. RESULTS Thirty-four consecutive patients were included. Complete or partial stone clearance after EHL was achieved in 24 patients (70.6%). Pancreatoscopy was not performed due to failure to cannulate the pancreatic duct (PD) (n=5) or resolution of stones after stent placement at index endoscopic retrograde pancreaticography (ERP) procedure (n=3). After successful PD cannulation, pancreatoscopy was technically successful in 24 out of 26 patients (92.3%). In one patient, the stone could not be visualized due to a resilient stricture. Complete stone clearance was achieved in 20 patients (80%), and partial in 5 patients (20%), after a median of 2 (IQR 2) ERP procedures and 1 (IQR 1) EHL procedure. In patients who underwent pancreatoscopy with EHL, mean Izbicki pain score at baseline was 62.3 ± 23.1 (n=25/25) and dropped significantly to 27.5 ± 35.0 (22/25) at 6 months' follow-up (p<0.001). The most common adverse event was acute pancreatitis, all mild and treated conservatively (n=7). CONCLUSION Pancreatoscopy-guided EHL is a promising treatment for symptomatic CCP patients with obstructive PD stones.