About 25–50% of patients with primary Sjögren's disease (SjD) take hydroxychloroquine (HCQ). Although it is widely prescribed, and recommended in international guidelines, its use is mostly based on expert opinion and personal experience. Our aim was to provide a comprehensive overview of the pathogenic mechanisms of HCQ, the current clinical evidence for its use, and its safety in primary SjD. HCQ plays an immunomodulatory and anti-inflammatory role, mainly by regulating some interferon proteins, chemokines, BAFF levels, and by modifying gut microbiota. It decreases immunoglobulins and ESR levels. In a Latin-American cohort, the main indications were arthritis, parotid gland enlargement and sicca-only symptoms. In the clinical setting, most studies showing a positive effect of HQC are open trials or retrospective cohorts. Some of these studies may be biased due to the use of non-validated outcomes, and a placebo response effect. To date, only 3 RCTs have investigated the benefits of HCQ, the JOQUER being the pivotal one. This study failed to improve oral/ocular symptoms or ESSDAI score. However, a re-analysis by symptomatology subgroups detected some differences in the ESSPRI. Recently, promising data from a small phase II RCT of the combination of HCQ/leflunomide was reported, but results should be replicated. Currently, the NECESSITY study is investigating treatment combinations that will provide new insights. In the meantime, HCQ plays a central role in the treatment of SjD due to its excellent benefit-risk profile. Data on damage accrual, quality of life, mortality and prevention of cardiovascular risks are also still lacking.