The WOC Initiative is a prospective study of 921 women of color (WOC) entering HIV care at nine (three rural, six urban) sites across the US. A baseline interview was performed that included self-reported limitation(s) in activity, health conditions, and the CDC's health-related quality of life measures (Healthy Days). One-third of the WOC reported limiting an activity because of illness or a health condition and those with an activity limitation reported 13 physically and 14 mentally unhealthy days/month, compared with 5 physically and 9 mentally unhealthy days/month in the absence of an activity limitation. Age was associated with a three- to fourfold increased risk of an activity limitation but only for WOC in the urban sites. Diabetes was associated with a threefold increased risk of a limitation among women at rural sites. Cardiac disease was associated with a six- to sevenfold increased risk of an activity limitation for both urban and rural WOC. HIV+ WOC reported more physically and mentally unhealthy days than the general US female population even without an activity limitation. Prevention and treatment of diabetes and cardiovascular disease will need to be a standard part of HIV care to promote the long-term health and HRQOL for HIV-infected WOC.