OBJECTIVES:  It is often thought that pharmaceutical companies target orphan indications to gain market entry at high prices prior to expanding into other indications. This study aims to evaluate the frequency of indication expansion among orphan designated drugs and if certain disease area entry strategies are more prone to indication expansion. METHODS:  Drugs approved from January 2005 to December 2015 (N=315) were obtained from the FDA website. FDA review classification and/or the FDA Orphan Drug Designations and Approvals Database was used to excluded from analysis drugs without orphan designation (n=202). Indication expansions from the remaining orphan designated drugs (n=113) were identified through review of FDA label updates. Each was catalogued to describe the setting, disease, and other descriptive characteristics. RESULTS:  30 of 113 (27%) orphan designated therapies experienced 1-3 indication expansion(s) following initial approval, 57% of which were oncology agents. Only 8 (27%) therapies had more than 1 indication expansion. Indication expansions could be categorized primarily into 6 categories: new indication into a different disease (57%), mutation status (17%), addition of combination therapy (17%), line of treatment (7%), increase age coverage (7%), and other (10%). More recently approved products (2011-2015) have had their 2^ndindication approved quicker than earlier products (2005-2010) with 9 drugs having subsequent indications approved within 3 years of initial launch compared to 5 years. Furthermore, the average number of indication expansions beyond initial indication can be seen increasing starting 2012 from a mean of 1 expansion in 2011 to 2.7 in 2014. CONCLUSIONS: Since 2005, only small subsets (27%) of orphan designated products have expanded into other indications. Oncology is the single disease area with the most expansion. Interestingly, the number of drugs with indication expansions has not increased over time. However, the most recent products (2011-2014) have shown an increase in multiple expansions.