Background: The purpose of this study was to understand the strategies employed by families that adopt Acquired Immune Deficiency Syndrome (AIDS)-orphaned children (Adoptive families) for coping with and mitigating the impact of AIDS in Mbeya Rural District, Tanzania. High numbers of AIDS-orphaned children aged below 18years in Mbeya Region have led to increasing the burden of families caring for them. Understanding the coping strategies and impact mitigation activities employed by adoptive families is important in order to develop programmes to help them. Methods: This study employed a qualitative method for data collection (one-on-one in-depth interviews). The respondents included 12 male and 8 female heads of families that provide essential care for AIDS-orphaned children in Mbeya Rural District in Tanzania. The framework approach was used to analyse the data that were collected from 15 July to 15 August 2010. Results: The study findings revealed that adoptive families faced several challenges including financial constraints due to increased needs for basic essentials such as health care expenses, school fees and food. Further impacts on adoptive families included shortage of work opportunities and limited time to address these challenges. To mitigate these challenges, adoptive families employed a range of coping strategies including selling family assets and renting out parts of cultivable land for extra cash. Task reallocation which involved the AIDS-orphaned children entering the labour force was also employed as a strategy to mitigate challenges and involved de-enrolling of children from schools so they could take part in income-generating activities in order to earn supplementary family income. The creation of additional income-generating activities such as poultry farming were other coping mechanisms employed, and these received support from both non-governmental organisations (NGOs) and governmental organisations, including the Isangati Agricultural Development Organization (local NGO) and the local government respectively. Conclusions: The current study identified challenges that adoptive families as well as the AIDS-orphaned children themselves faced in Mbeya Rural District, Tanzania. Recognition of these issues highlights the need for targeted interventions to address the underlying social determinants of human immunodeficiency virus or HIV and AIDS in affected populations in order to prevent further imposition of social, cultural and economic disadvantages on families that provide care for AIDS-orphaned children and the children themselves. These findings may prove useful in provoking discussions that may lead to HIV/AIDS prevention and the development of broader mitigation strategies to alleviate the impact of this scourge on families and communities in rural Tanzania, and in similar settings across the world.