This study attempted to explore and describe the gender and work challenges People with Disabilities (PWDs) encountered in their participation in Income Generating Activities (IGAs) in the informal sector of Uganda. The study showed that in spite of being disadvantaged in society, PWDs have joined the informal sector in varying capacities in an attempt to earn a living. However, little is known about the conditions under which PWDs join and remain in the informal sector; how they acquire capital and other resources. Not only did the challenges that PWDs encounter impact negatively on their profits, but they could also potentially jeopardise their future existence of the IGAs of PWDs that have small turnovers and low profit margins. This without doubt indicates that PWDs in the informal sector need socio-economic resources for their IGAs as well as disability grants to cater for their pressing needs given that many of them are heads of households and single parents.