BackgroundActinic keratosis (AK) is a common premalignant skin lesion, and topical 5-fluorouracil (5-FU) is commonly used in field-directed therapy. However, 5-FU is associated with frequent local skin reactions.ObjectiveThis study aimed to qualitatively assess experiences among patients with AK who refuse retreatment with 5-FU.MethodsSemistructured interviews were conducted with 10 adult participants who had received treatment with 5-FU for AK between January 1, 2017, and January 1, 2020, and refused future treatment with 5-FU. Results were analyzed using qualitative research methods.ResultsAlthough most participants had low concern upon having received a diagnosis of AK, most felt that treatment is very important. When initiating treatment with 5-FU, most cited recommendation by their health care professionals as the primary motivator and initially had low concern regarding treatment. The side effects associated with treatment were physically and psychosocially burdensome for most participants and led to temporary lifestyle adjustments. After treatment, most did not believe that their health care provider prepared them for treatment or were unsure. While half of the participants felt that 5-FU helped treat AKs, half were either unsure, due to premature discontinuation, or did not think that 5-FU treated their AKs.Conclusions5-FU is one of the most commonly prescribed treatments for AKs, yet most patients experienced both a physical and psychosocial burden with the treatment. Inability to assess efficacy due to premature discontinuation secondary to 5-FU–related reactions is common, and shared decision-making, navigating treatment options, and taking into account patient preferences may be critical to help assure better adherence and outcomes. Although our study was limited by input from participants who refused future treatment with 5-FU, most stated that they would still continue to seek treatment for AKs in the future and would consider other topical treatments, especially if associated with a milder tolerability profile.