Aim: Hydroxychloroquine (HCQ), commonly used to treat patients with primary Sjögren's syndrome (pSS), has been shown to delay the development of systemic lupus erythematosus (SLE). This study aimed to explore the association between HCQ use and future development of SLE in pSS patients based on a nationwide nested case–control study. Method: Based on the National Health Insurance Research Database of Taiwan, those patients who were diagnosed with SLE at least 1 year after the diagnosis of pSS were identified as cases. Matched controls were randomly selected from pSS patients without a later diagnosis of SLE in a 1:10 ratio. The odds ratios (ORs) of HCQ exposure between cases and controls were analyzed by unconditional logistic regression after adjustment for age. Results: A cohort of 11 772 pSS patients were extracted from the database during the period from January 1, 2000 to December 31, 2010. A total of 111 (0.9%) pSS patients developed SLE during the follow-up period. Most (79%) of them developed SLE within 5 years after the diagnosis of pSS. There was no significant difference in the odds of HCQ exposure between cases and controls, with an adjusted OR of 2.43 (95% CI: 0.73–8.05). Neither did we observe a significant difference in the odds of exposure to a higher average dose of HCQ (≥100 mg/d vs non-exposed) between cases and controls in the sensitivity analysis. Conclusion: Nearly 1% of pSS patients may develop SLE. HCQ use in pSS patients was not associated with a lower possibility of the future development of SLE.