Participants refusal to take part in research is an unpleasant experience that investigators face. This paper highlights some of the reasons why people from resource-poor settings refuse to take part in health research. This paper also highlights standards which investigators can adopt to avoid unnecessary refusals and at the same time ensure that individuals have the right to participate and freedom to refuse. Our objective was to explore reasons why people refuse to join research studies. We conducted focus group discussions with people who had refused to take part in a number of biomedical research studies but agreed to be interviewed in this study. The study was undertaken in the peri-urban and urban areas of Blantyre district; Bangwe, Mpemba and Madziabango. We found nine key factors that influence people to refuse to participate in biomedical research. The factors are failure to follow traditional customs, lack of study benefits, superstition, poor informed consent procedures, ignorance of health research, fear of strangers, lack of cultural sensitivity, poor timing, and previous bad research experience. People refuse to participate in health research for a number of reasons which can be overcome if researchers embark on community engagement before implementing their studies.