The aim of this work was to clarify the effect of leflunomide (LEF) on the eye dryness in patients with secondary Sjögren's syndrome associated with rheumatoid arthritis (RA-sSS) and in patients with rheumatoid arthritis (RA). Seventy-five female patients, 45 with RA-sSS (group A) and 30 with RA (group B), taking methotrexate at a dose of 20 mg/week for more than 6 months were enrolled in this study. They all had a loading dose of leflunomide then were maintained at a dose of 20 mg/day in addition to methotrexate for another 3 months. The modified disease activity score (DAS28) was calculated and modified Schirmer's-I test was performed. Assessment of disease parameters was done to all patients before and after 3 months of taking LEF. The mean modified Schirmer's-I test showed a significant decrease after 3 months of taking LEF in group A (3 ± 1.6 before versus 1.9 ± 1.6 after 3 months, P < 0.001), while this difference was non-significant in group B (21.3 ± 10 versus 19.9 ± 11). One patient (group A) developed peripheral ulcerative keratitis (PUK) with exacerbation of disease activity (DAS-28 = 6.9) that improved by taking corticosteroids. Three patients (group A) had aggravation of punctate keratocojunctivitis sicca with punctate erosions without PUK. The condition improved dramatically by stopping LEF and using topical lubricants. We report in this study a significant deterioration of the eye dryness in patients with sSS-RA after 3 months of receiving LEF inspite of the significant improvement of their DAS28. This finding was not clearly detected in RA patients. Close monitoring of eye dryness changes by special tests in patients using LEF is recommended, especially in cases with sSS-RA having very low baseline values.