This study investigated the influence of two different treatments for a kidney inflammation (i.e. proliferative lupus nephritis) on health-related quality of life (HRQoL) in patients with the chronic auto-immune disease systemic lupus erythematosus (SLE). One treatment protocol, the National Institutes of Health (NIH) protocol, was characterized by a high dose of cyclophosphamide (CYC, an immunosuppressive drug), and the second treatment, the Euro-Lupus protocol, involved a low-dose CYC. Thirty-two SLE patients were included based on the received treatment for an episode of proliferative lupus nephritis, according to either the Euro-Lupus or the NIH protocol. The two groups were compared on HRQoL as measured by the SF-36 and the SLE Symptom Checklist (SSC). The Euro-Lupus group (N = 16) tended to show a higher HRQoL than the NIH group (N = 16) on four of seven scales of the SF-36. In addition, the Euro-Lupus group experienced less burden from nausea or vomiting than the NIH group as assessed by the SSC. Fatigue was the most disturbing symptom in both groups. The most burdensome aspects of treatment were related to chemotherapy (55.2%) and use of prednisone (34.5%). Patients with a low HRQoL and high levels of fatigue were more likely to have low levels of serum complement C4 (i.e. elevated immune activity). In conclusion, patients who are treated according to the Euro-Lupus protocol may experience a higher HRQoL than patients who receive the NIH treatment. However, chemotherapy remains burdensome in the low-dose treatment regimen. Potential interventions to further enhance the HRQoL in SLE patients with proliferative lupus nephritis are discussed.