This study investigates whether using an HIV/AIDS symptom management manual with self-care strategies for 21 common symptoms, compared to a basic nutrition manual, had an effect on reducing symptom frequency and intensity. A 775-person, repeated measures, randomized controlled trial was conducted over three months in 12 sites from the United States, Puerto Rico, and Africa to assess the relationship between symptom intensity with predictors for differences in initial symptom status and change over time. A mixed model growth analysis showed a significantly greater decline in symptom frequency and intensity for the group using the symptom management manual (intervention) compared to those using the nutrition manual (control) (t=2.36, P=0.018). The models identified three significant predictors for increased initial symptom intensities and in intensity change over time: (1) protease inhibitor-based therapy (increased mean intensity by 28%); (2) having comorbid illness (nearly twice the mean intensity); and (3) being Hispanic receiving care in the United States (increased the mean intensity by 2.5 times). In addition, the symptom manual showed a significantly higher helpfulness rating and was used more often compared to the nutrition manual. The reduction in symptom intensity scores provides evidence of the need for palliation of symptoms in individuals with HIV/AIDS, as well as symptoms and treatment side effects associated with other illnesses. The information from this study may help health care providers become more aware of self-management strategies that are useful to persons with HIV/AIDS and help them to assist patients in making informed choices.