Sex workers are considered a high-risk group for sexually transmitted infections, including human immunodeficiency virus (HIV), and are often targeted by prevention interventions with safer sex messages. The purpose of this study was to explore the extent to which knowledge of HIV and perception of risk influence safer sex practices among female sex workers (FSWs) in Port Moresby, Papua New Guinea. FSWs (n = 174) were recruited from 19 sites to participate in the study. Qualitative data were collected using semistructured interviews with FSWs (n = 142) through focus group discussions and (n = 32) individual interviews. In addition, quantitative data were collected from all FSWs using a short structured, demographic questionnaire. Data were analyzed using recurring themes and calculations of confidence intervals. Despite some common misperceptions, overall, most FSWs were basically aware of the risks of HIV and informed about transmission and prevention modalities but used condoms inconsistently. Most reported using condoms ‘sometimes’, almost one-sixth ‘never’ used condoms, only a fraction used condoms ‘always’ with clients, and none used condoms ‘always’ with regular sexual partners (RSPs). Among these FSWs, being knowledgeable about the risks, transmission, and prevention of HIV did not translate into safe sex. The findings suggest that certain contextual barriers to safer sex practices exist. These barriers could heighten HIV vulnerability and possibly may be responsible for infection in FSWs. Specific interventions that focus on improving condom self-efficacy in FSWs and simultaneously target clients and RSPs with safer sex messages are recommended