The purpose of the present study was to describe HIV-infected patients' self-reported health-related quality of life (HRQOL) in relation to sense of coherence over a 24-month period. A total of 104 HIV-infected patients (71% males) answered questionnaires at three times at 12-month intervals. At the same time, clinical characteristics were collected from the patients' medical records. HRQOL was measured by the HIV-symptom scale, the Health Index, and the Well-Being Scale. Coping ability was measured with the 29-item sense of coherence (SOC) scale. The patients were divided into three groups depending on SOC scores (low, moderate, high). The results indicate that the group with low SOC scores rate their HRQOL worse than the other groups at all three measurements (p values from <0.05 to <0.001). Over the 2-year period, the patients' CD4 cell count/mm3 increased significantly (p values <0.001), indicating good response to antiretroviral treatment. However, their HRQOL did not improve during these 2 years. Patients with higher SOC rate their HRQOL better than those with a lower SOC, during these years. Future studies should investigate the predictive value of the SOC scale of HRQOL in HIV-infected patients.