Purpose: The optimal timing of Highly Active Antiretroviral Therapy (HAART) initiation in chronic HIV infection is unclear. HAART may have a negative effect on quality of life (QoL) due to toxicities and pill burden. The extent to which these potential negative effects of HAART are outweighed by the positive effect of delay of disease progression may depend upon the timing of HAART initiation. We investigated the effect of HAART on QoL among patients starting HAART at different CD4-cell counts. Methods: Naive patients initiating HAART, enrolled in the ATHENA-cohort between 1998 and 2000, completed the MOS-HIV health survey at enrolment and every six months thereafter until June 2005. Patients were categorized according to their baseline CD4 cell count into a group with >350 CD4-cells/無, 201-350 CD4-cells/無, and <200 CD4 cells/無. We investigated whether there was a different pattern of change over time in physical- and mental health summary scores between the three groups using mixed linear models. Results: A total of 265 patients enrolled in the study. The mean (SD) age was 39 (8) years and 93% were males. The median plasma HIV RNA was 4.8, 5.0, and 5.2 log10 copies/ml in the three groups, respectively. At baseline, patients who initiated HAART with <200 CD4-cells/無 (n=116) had significantly worse physical health compared to those who initiated HAART with 201-350 CD4-cells/無 (n=79) and with >350 CD4-cells/無 (n=70). We found a statistically significant different pattern of change over time in physical health between the three groups. Patients who started HAART with <200 CD4 cells/無 had significantly more improvement in physical health over time than patients who started HAART with 201-350 CD4-cells/無 or with >350 CD4-cells/無. No difference in pattern of change over time was found for mental health with all three groups showing significant improvement. Conclusions: Patients who initiated HAART with <200 CD4-cells/無 showed more pronounced improvements in QoL compared to those who initiated HAART with >200 CD4-cells/無. We found no clear advantage regarding QoL of starting HAART with 201-350 CD4-cells/無 compared to starting HAART with >350 CD4-cells/無. Although QoL should be taken into account when deciding about HAART initiation in the individual patient, it will not likely be a decisive factor on a group level among patients with more than 200 CD4-cells/無.