Objective: Peripherally inserted central catheters (PICC) are frequently used to deliver medical therapies, but our knowledge regarding PICC-related complications remains incomplete. The objective of this study was to systematically elicit and characterise PICC-related complications as experienced by patients during and after hospitalisation. Design: Prospective cohort study. Setting: Inpatient medical units at four US hospitals in two states. Participants: Consecutive sample of patients who had a new PICC placed during a hospital stay between August 2015 and May 2017. Main outcome(s): Patient-reported signs and symptoms of a possible PICC-related complication or functional issues. Results: Of the 438 patients in the analytic cohort (91.4% of those consented), two-thirds were male with a mean age of 56 years. The most common reason for PICC placement was long-term antibiotic therapy (43.4%). During the 70-day follow-up period, 61.4% of patients reported signs of at least one complication, including potentially serious complications, such as bloodstream infection (17.6%) and deep vein thrombosis (30.6%). Correspondence of these reported events with medical record documentation of the complication was generally low. More than one-quarter (27.9%) of patients reported minor complications, such as insertion site redness, discomfort or difficult removal. While the PICC was in place, 26.0% reported restrictions in activities of daily living, 14.4% social activity restrictions and 19.2% had difficulty with flushing or operating the PICC. Conclusion: Over 60% of patients report signs or symptoms of a possible complication or adverse effect after PICC placement. Bothersome complications from the patient perspective are clearly more common than those that typically rise to the level of healthcare provider attention or concern. Understanding the patient experience is critical for providing safe and effective care.