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Abstract Background A sizeable number of HIV-infected patients receiving HAART do not maintain prolonged virologic suppression. We evaluated long-term HIV viral load (VL) responses to HAART as a risk factor for AIDS events (AE) that is independent of CD4 responses. Methods A cohort of patients with pre-therapy CD4 < 200/mm3 who had CD4 and VL measurements for > one year after receiving HAART at a university clinic were prospectively enrolled. Cox proportional multivariate regression model was used to determine whether CD4 and VL responses were independently associated with new AE. Results The patient (N = 214) mean baseline CD4 = 92/mm3, VL = 219,000 c/mL and follow-up duration 42.3 months (range 13–72 months). A new AE occurred in 56 patients; CD4 cell count response to HAART that remained < 200/mm3 throughout the study period was a significant risk factor for new AE (RR = 9.7–12.5; p < 0.001). Similarly, VL responses that remained > 5,000 c/mL during this period was also a significant risk factor (RR = 6.7–12.8; p = 0.001) that was independent of CD4 response adjusted for <> 200/mm3. Conclusion Maintaining adequate long-term virologic responses to HAART provides a clinical benefit independent of CD4 responses.