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Introduction Semirigid thoracoscopy plays an important role in the diagnosis of pleural diseases. However, its diagnostic performance remains unsatisfactory particularly in terms of the negative likelihood ratio. Therefore, more effective supplementary diagnostic tools are required. Probe-based confocal laser endomicroscopy (pCLE), which allows live tissue imaging at the cellular level, can discriminate between malignant and benign pleura during medical thoracoscopy. However, the clinical relevance of pCLE in pleural disease remains unclear. This protocol describes a randomised controlled trial that evaluates the additional diagnostic value of pCLE in diagnosing pleural diseases using semirigid thoracoscopy.Methods and analysis This study is a multicentre, parallel-group, randomised controlled trial that will be conducted at ten sites in China. A total of 158 adult patients with undiagnosed exudative pleural effusions will be enrolled and randomly allocated (1:1) to undergo either a conventional pleural biopsy (control group) or a pCLE-guided pleural biopsy (intervention group) via semirigid thoracoscopy. In the intervention group, a pCLE system will be applied during thoracoscopy to identify suspicious pleural areas for targeted biopsy. The primary outcome is the diagnostic yield of the procedure in patients with unknown causes of pleural effusion. Secondary outcomes include negative likelihood ratio, diagnostic sensitivity in specific diseases, procedural time, rate of adequate specimens for achieving molecular diagnosis and complications.Ethics and dissemination Ethics approval was obtained from the China-Japan Friendship Hospital Ethics Committee (2025-KY-018). Written informed consent will be obtained from all the participants. The findings will be disseminated through journal publications and conference presentations.Trial registration number NCT06741839.