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Purpose The aim was to study the prevalence and related risk factors of dry eye disease (DED) in a random population sample from Cairo and upper Egypt. Materials and methods A clinic-based, cross-sectional, observational, multicenter study was conducted on eyes of healthy individuals accompanying ophthalmological patients coming for ocular examination in outpatient clinics of Ain Shams University Hospital and Al Watany Eye Hospital, Cairo; Saint Mary Hospital, Qena; and Aswan Eye center, Aswan, Egypt. Eyes were selected by systematic random sampling. Two questionnaires were used: the Ocular Surface Disease Index and another one covering medical history and risk factors for DED. External ocular examination, tear film break-up time, and Schirmer's tests were done. Diagnosis of DED was established on an Ocular Surface Disease Index score of 50 or above associated with at least one of DED symptoms together with either tear film break-up time of less than or equal to 5 s or Schirmer's test measurement of less than or equal to 10 mm. Results A total of 603 eyes were included; 290 of which were of male participants and 313 were of female ones. The age range was 18–94 years, with a mean age of 50.06±19.06 years. The prevalence of DED was 77.6% (468 eyes). There was a statistically highly significant difference in DED prevalence among all age groups (P<0.0001), with higher prevalence in age group of 41–50 years old, but the trend between consecutive age groups was not statistically significant (P=0.4747). Moreover, DED was statistically more common in females [86.9% of female participants versus 67.6% of male participants (P<0.0001)]. Blepharitis was found in 81% (379 eyes) and smoking in 43.8% (205 eyes). Moreover, 29.7% (139 eyes) of detected DED cases had associated dry mouth. Conclusion DED was quite common among our studied subjects, and most of them had associated blepharitis. Smoking was also a major risk factor. Moreover, DED was more common in female sex. There was a statistically significant difference in DED prevalence among the age groups. [ABSTRACT FROM AUTHOR]