Parents and caretakers of young children often have concerns about vaccine safety and adverse events following immunization (AEFI). Little is known about vaccine safety perceptions in Uganda and their influence on parental decision-making about infant immunization. The study objectives were: to identify community sources of information on immunization, vaccine safety and AEFI; determine caretakers' knowledge of immunization; identify community concerns/fears about immunization and AEFI and their influence on caretakers' decisions to vaccinate; and obtain an understanding of knowledge, perceptions, and experience of health care workers (HCWs) and policy administrators on vaccine safety and AEFI. Twelve focus group discussions with 136 caretakers who were very or somewhat concerned about vaccine safety and 25 key informant interviews were conducted in two districts (1 urban and 1 rural) with district authorities and health facility staff as well as national level decision-makers between December and April 2006. Content analysis was used to analyze the results. The main themes identified related to general lack of information among caretakers about immunization, perceived immunization benefits, immunization concerns, and misconceptions. Specific caretaker concerns related to vaccine administration, immunization services and vaccine safety. Experiences with AEFI and concerns about vaccine safety negatively affected caretakers' decisions to vaccinate their children, notably in rural areas. HCWs demonstrated knowledge about AEFI and their management although incidences reported to facilities were rare. Inadequate communication between HCWs and caretakers was noted. Concerns and misconceptions about vaccination still exist among caretakers in Uganda and influence decisions to vaccinate. Effective inter personal communication initiated by HCWs towards caretakers is needed.