Background: Early diagnosis of primary Sj & ouml;gren's syndrome (pSS) remains difficult due to its insidious onset. Objectives: To identify whether meibomian gland dropout (MGD) is a sensitive and noninvasive predictor of pSS by studying its association with histopathology in labial salivary gland biopsy in patients with clinically suspected pSS. Design: Prospective, randomized, multicenter, comparative effectiveness study. Methods: The study was conducted from July 2022 to July 2023. In all, 56 eligible participants with clinically suspected pSS were recruited from three combined ophthalmology medicine/rheumatology SS clinics. All participants with suspected pSS were evaluated and diagnosed by ophthalmology and rheumatology consultants and underwent infrared imaging of the meibomian glands using Keratograph 5M and histopathological evaluation of labial salivary gland biopsies. The length, width, and tortuosity of the meibomian glands were measured; the dropout rate in the nasal, temporal, and total eyelids was analyzed; and the dropout score was calculated using meibography grading scales. Results: Among the 56 participants, 34 were identified with pSS, and 22 were diagnosed with non-SS dry eye (NSSDE) and served as the control group. We recorded significant differences in the temporal and total MGD rates of the upper eyelids between the pSS and NSSDE groups (all p < 0.01). Improved prediction accuracy was achieved with the temporal and total MGD rates in the upper eyelids, with area under the curve values of 0.94 and 0.91, and optimal cutoff points of 0.78 and 0.75, respectively. Conclusion: MGD in the upper eyelids, especially in the temporal portion, is strongly associated with the histopathological outcome of labial salivary gland biopsy in pSS and is proposed as a highly predictive and noninvasive biomarker for the early diagnosis of pSS.