Objective To study the prevalence and impact of comorbidities among a cohort of patients with systemic lupus erythematosus (SLE). Methods This study is retrospective, multicenter including 902 Egyptian patients with SLE. Medical records were reviewed for demographic data, clinical characteristics, routine laboratory findings, immunological profile, and medications. Moreover, SLE Disease Activity Index (SLEDAI), and the Systemic Lupus International Collaborating Clinics/American College Rheumatology Damage Index scores were calculated. Results Comorbidities were found in 75.5% of the studied group with hypertension and dyslipidemia as the most frequent comorbidities (43.1% and 40.1%, respectively), followed by sicca features, avascular necrosis, diabetes, osteoporosis and renal failure (11.5%,9%, 9%,8.9%, and 7.1%, respectively). Multivariate regression model showed statistically significant relation between the presence of comorbid condition and each of age ( P = 0.006), disease duration ( P = 0.041), SLEDAI at onset ( P < 0.001), cyclophosphamide intake ( P = 0.001), and cumulative pulse intravenous methylprednisone ( P < 0.001). Also, when adjusted to age and sex, those with multiple comorbid conditions had 18.5 increased odds of mortality compared to those without comorbidities (odds ratio (OR), 95% confidence interval (CI) = 18.5 (6.65–51.69)]. Conclusion Patients with SLE suffer from several comorbidities, with an increasing risk with age, longer disease duration, higher SLEDAI at onset, cyclophosphamide intake and cumulative pulse intravenous methylprednisone. Risk of mortality is exponentiated with multiple comorbidities.