Purpose: To compare between the effectiveness of systemic azithromycin and topical tea tree oil in treating posterior marginal blepharitis. Design: prospective comparative research. Participants: sixty cases suffering from posterior marginal blepharitis, assigned into 2 groups, each one comprised thirty cases. Methods: Group I applied TTO once daily at bedtime. Group II administered oral azithromycin once daily before breakfast for six days and all patients applied topical lubricant eye drops five times daily. The tear film break-up time, ocular symptoms, Schirmer's test and eyelid margin signs have been assessed at baseline and five weeks later. Results: Each group was sub-divided into (severe) and (mild to moderate) sub-groups, then we compared the baseline data of (severe) sub-groups and (mild to moderate) sub-groups. Insignificant variance was observed in results regarding symptoms, signs, Schirmer's test and TBUT. Five weeks after receiving treatment, we collected patients' data same as first visit. We compared the data in first and second visits in each sub group and significant variance was observed in both groups. We compared results in severe sub-groups, significant variance was observed regarding symptoms (p < 0.001), signs (p < 0.001), TBUT test (p < 0.001) and Schirmer's test (p < 0.001). We compared results in mild to moderate sub-groups and significant variance was observed according to symptoms (p < 0.001), signs (p < 0.001), TBUT test (p < 0.001) and Schirmer's test (p < 0.001). Conclusions: Both TTO and oral azithromycin are effective in treating posterior marginal blepharitis with higher efficacy of TTO.