OBJECTIVES: Given similar cure rates and acquisition costs, the question of real world tolerability for the current class of hepatitis C medications is of great interest. To explore post-marketing safety profiles we estimated downstream direct medical costs related to adverse events (AEs) and poor patient outcomes associated with these drugs. METHODS: We analyzed 1) AE and outcome-specific medical costs obtained from AHRQ, 2) AE and outcome data from FDA’s Adverse Event Reporting database (FAERS), and 3) drug usage information from Evaluate Pharma. ICD-9 codes were mapped to MedDRA Preferred Terms by the use of BioPortal and ICD9Data.com. Focus was limited to EudraVigilance Important Medical Event AEs and “primary suspect” AE drug reports. In cases with more than one eligible AE, only the AE with the largest individual cost was selected. In cases with no eligible AE, but with a listed outcome, only the largest outcome cost was used. Individual report costs were summed for each drug and then divided by exposure rates to obtain downstream costs per patient. It should also be noted that under reporting to FAERS may result in under estimation of projected downstream costs. Three hepatitis C drugs were analyzed in detail. RESULTS: Our estimated direct medical costs per patient exposed showed a large range: ledipasvir and sofosbuvir ($65); sofosbuvir ($75); and ombitasvir, paritaprevir, ritonavir, and dasabuvir ($151). CONCLUSIONS: Strict patient adherence to hepatitis C treatment regimens is very important from both efficacy and cost standpoints. Adherence can be significantly affected by side effects. Our cost estimates based on these events suggested that ledipasvir and sofosbuvir result in less downstream medical costs than sofosbuvir, and especially ombitasvir, paritaprevir, ritonavir, and dasabuvir. We look forward to re-assessing these data based on future case reports as these drugs become even more widely prescribed.