BACKGROUND : Malaria control remains a leading health challenge in Mozambique. Indoor residual spraying (IRS) is an effective strategy to control malaria transmission, but there are often barriers to reaching the coverage necessary for attaining maximum community protective effect of IRS. Mozambique recorded a high number of household refusals during the 2016 IRS campaign. This study sought to evaluate household and community factors related to the acceptability of IRS to inform strategies for future campaigns in Mozambique and the region. METHODS : A cross-sectional, qualitative study was conducted in eight urban and rural communities in two high malaria burden provinces in Mozambique. Data were collected through in-depth interviews with community members, leaders, sprayers, and representatives of district health directorates; focus group discussions with community members who accepted and who refused IRS during the 2016 campaign; systematic field observations; and informal conversations. Data were systematically coded and analysed using NVIVO-11®. RESULTS : A total of 61 interviews and 12 discussions were conducted. Community participants predominantly described IRS as safe, but many felt that it had limited efficacy. The main factors that participants mentioned as having influenced their IRS acceptance or refusal were: understanding of IRS; community leader level of support; characteristics of IRS programmatic implementation; environmental, political and historical factors. Specifically, IRS acceptance was higher when there was perceived community solidarity through IRS acceptance, desire to reduce the insect population in homes, trust in government and community satisfaction with past IRS campaign effectiveness. Participants who refused were mainly from urban districts and were more educated. The main barriers to acceptance were associated with selection and performance of spray operators, negative experiences from previous campaigns, political-partisan conflicts, difficulty in removing heavy or numerous household assets, and preference for insecticide-treated nets over IRS. CONCLUSIONS : Acceptance of IRS was influenced by diverse operational and contextual factors. As such, future IRS communications in targeted communities should emphasize the importance of high IRS coverage for promoting both familial and community health. Additionally, clear communications and engagement with community leaders during spray operator selection and spray implementation may help reduce barriers to IRS acceptance.