Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with poor 5-year overall survival. This can be mainly explained by late diagnosis mostly at advanced stages, excluding primary tumor resection as putative curative treatment, and a profound therapy resistance. L1 cell adhesion molecule (L1CAM) is upregulated in PDAC cells and associated with different hallmarks of cancer contributing to tumor progression and therapy resistance. Using L1CAM as tumor associated antigen, two antibody drug conjugates (ADC) targeting L1CAM were developed with different toxins as payload. Both L1CAM-ADC led to a L1CAM specific reduction in tumor cell growth of up to 60% in 2D PDAC cell models. A maximum therapeutic effect was observed when at least 50% of the PDAC cells expressed L1CAM. In 3D PDAC spheroids, MMAE conjugated L1CAM-ADC still showed strong therapeutic effects, while efficacy of SG3199 conjugated L1CAM-ADC was diminished. Co-culture of PDAC spheroids with pancreatic myofibroblasts did almost not impair L1CAM-ADC anti-tumor effects, while macrophages enhanced anti-tumor responses. Application of L1CAM-ADC as adjuvant or palliative treatment in clinically adapted PDAC mouse models exerted potent anti-tumor effects even with enhanced tumor burden. Adjuvantly applied, MMAE conjugated L1CAM-ADC efficiently reduced pancreatic relapses and peritoneal metastases, whereas SG3199 conjugated L1CAM-ADC less impacted pancreatic relapses, but almost completely eliminated liver and peritoneal metastases. In the palliative setting, both L1CAM-ADC reduced number and size of liver and peritoneal metastases. Overall, our results demonstrate strong anti-tumor effects of L1CAM-ADC underscoring their potential as immunotherapeutic approach in therapy of even advanced PDAC.