Background: SSAs are the most common treatment for well-differentiated NETs. Side effects include biliary and GI disorders, injection-site pain and hyperglycemia. There is often misdiagnosis or delayed diagnosis of PEI pts receiving SSAs, as confused with disease progression or SSA failure. This is the largest study to describe the incidence of PEI secondary to SAAs in NET. Methods: A total 160 pts treated with SSAs for NETs were identified. Data including demographics, pathology, stage, pharmacy records (dose/duration of long and short-acting SSAs, use of antidiarrheal, pancreatic enzyme replacement therapy (PERT), proton pump inhibitors (PPI) or H2-Receptor antagonist (H2RA) was collected. Laboratory data include chromogranin A (CgA), 5-HIAA in urine (110) and serum (50), quantitative fecal fat test (QFFT) or fecal elastase (FE-1). PEI was defined by a FE-1 below 200 μg/g or QFFT> 21gm/72hr. Results: Of 160 pts, 134 received Octreotide and 26 Lanreotide. Of these, 23 also received short-acting SSA for worsening diarrhea, 96 had intensification of antidiarrheals and 1 got telotristat. A nutritionist and/or gastroenterologist evaluated 79 pts. In pts with worsening diarrhea despite stable or improved CgA/5-HIAA, QFFT was performed in 47 pts and FE-1 in 50 pts. FE-1 confirmed PEI in 8, QFFT in 19, 27 based on clinical diagnosis, and 16 had sample error or refusal. CTCAE v4.0 grades (G) of PEI in these pts were: G2 (69%), G3 (22%) and G4 (9%). Median time to development of PEI was 12 months (range 3 - 32). Except 1 pt (religious), 53 received PERT either with concomitant PPI (50) and 2 H2RA. Response was evaluable in 110 pts; 78% had PEI improved within 4-8 weeks. 2 pts were non-compliant and another 3 had motility disorders. Conclusions: SSA-induced PEI occurs in 34% of pts. This is the largest study addressing this under-diagnosed but relevant complication of SSAs. SSAs may inhibit secretion and release of amylase, trypsin, lipase, secretin, CCK, motilin, bile acid leading to PEI. Clinicians should actively identify and treat this toxicity to improve diarrhea and weight loss in these pts.