Guntur district in Andhra Pradesh, south India, has over 10 000 female sex workers (FSWs), of whom one fifth are estimated to be HIV infected. Following implementation of the Bill & Melinda Gates Foundation funded India AIDS prevention initiative, Avahan, we conducted qualitative studies with FSWs in Guntur district to examine in-depth, perceptions, behaviour and issues pertaining to their vulnerability to HIV infection. Three focus group discussions and 40 in-depth interviews were conducted with 60 FSWs, selected by random sampling. The study found evidence that client solicitation practices are changing in Guntur district, with sex workers now soliciting clients in their homes, often using mobile phones, or at their workplace, rather than in brothels or in public places. In addition, clients are most frequently requesting anal instead of vaginal sex, possibly resulting from recent exposure to pornography. FSWs were frequently unaware that unprotected anal intercourse put them at risk of HIV or other STIs, and the majority reported unprotected anal intercourse with their clients. Older FSWs and HIV-infected FSWs reported living in extreme poverty and were particularly vulnerable, often agreeing to unprotected vaginal and anal intercourse to earn enough money to survive. This, coupled with sharing of clients by home-based FSWs, suggests continued and changing vulnerability in this setting where many FSWs are already HIV infected and where understanding of risk appears deficient. Monitoring the changing sex work environment and adapting programmes accordingly will be crucial if HIV prevention programmes are to continue to reach these target populations effectively.