Over the past 60 years, overall mortality in systemic lupus erythematosus patients has dramatically decreased, but late mortality, which relates to the damage caused by the disease, its treatments and/or evolving comorbidities, is still high. This is particularly true in patients with late-onset lupus, a special subgroup of patients who, despite not having very active disease, experience a larger number of comorbidities, and higher damage accrual and mortality rates than early-onset patients. Treating these late-onset patients can be more difficult due to the risk of drug-drug interactions and aging-related processes. Antimalarials should be used whenever possible, and glucocorticoids and immunosuppressive drugs must used be carefully, especially in this population. NSAIDs should be avoided if possible. Adequate treatment of comorbidities should improve these patients' prognoses.