Abstract Background Alexithymia has been described as an important dimension in several medical diseases. Systemic lupus erythematosus (SLE) is a chronic condition characterized by unpredictable clinical manifestations. Our aim is to reveal which factors (psychological factors and quality of life dimensions) are associated with alexithymia in SLE patients. Methods Fifty-three sequential SLE patients (ACR criteria) and 41 asthma patients were studied by means of validated scales for alexithymia (Toronto Alexithymia Scale), psychopathology (Brief Symptom Inventory, Hospital Anxiety and Depression Scale), personality dimensions (NEO-FFI), and quality of life (Short Form-36 Health Survey). Systemic lupus erythematosus patient's clinical and laboratorial evaluation was performed by indicators of activity (Systemic Lupus Erythematosus Disease Activity Index) of accumulated damage (Systemic Lupus International Collaborating Clinics/ACR Damage Index), length of disease, and therapy. Results An association between alexithymia and psychopathological symptoms, and personality and quality of life dimensions was found. By means of multiple regression analysis, openness and depression were the 2 predictors for alexithymia in SLE patients. We found a high prevalence rate of alexithymia in SLE patients; however, when controlling for depression symptoms (Hospital Anxiety and Depression Scale–Depression, <7), we found a lower percentage of alexithymic traits than that of the total sample of SLE. Conclusion Alexithymia was associated with psychological distress and with quality of life impairment. Understanding the role of psychological factors in SLE patients may contribute to a more comprehensive perspective of the disease, its impact on patient's daily routine, and how patients adapt emotionally to a chronic disease.