The aim of the study was to assess the effects of Sense of Coherence (SOC), emotional distress and treatment adherence on disease activity and functioning level of persons with systemic lupus erythematosus (SLE). One hundred persons with SLE, aged 18-60, participated in the study. They responded to the SOC scale, hospital anxiety and depression scale (emotional distress) and to questionnaires about adherence to treatment, level of functioning and disease activity. The results show a moderate level of disease activity and everyday functioning, as well as moderate levels of emotional distress. Income, emotional distress and adherence significantly predicted the levels of functioning (p < 0.001), while income and emotional distress significantly predicted the levels of disease activity only (p < 0.001). SOC was significantly associated with higher level of functioning (p < 0.001) and lower disease activity (p < 0.01), while emotional distress, but not treatment adherence, highly mediated these relationships. The results emphasize the associations of emotional distress and SOC with severity of the symptoms and level of functioning, and the associations between SOC and adherence to treatment. Further confirmation of the results with larger samples and longitudinal designs are warranted.