OBJECTIVE: To preliminarily explore the potential effect of β-glucan on Chinese medicine (CM) concept protective qi deficiency (PQD), and the methodology for future definitive studies. METHODS: To have a standardized assessment of PQD, a list of 13 potentially PQD-relevant parameters were firstly created, each with defined quantitative or categorial scales. Using the data from 37 participants with (21 cases) or without (16 cases) PQD, multivariate logistic modeling was conducted to create a preliminary diagnostic PQD risk score. Subsequently, 21 participants diagnosed with PQD were treated with β-glucan in a dose of 200 mg/day for 8 weeks. Data were collected for trial acceptability measures (rate of recruitment, withdrawal, and compliance), and the participants were assessed for PQD status at baseline and every 2 weeks thereafter. RESULTS: The preliminary logistic model consisted of 3 parameters (low voice and apathy, aversion to wind and cold, and Cun pulse). The resulting risk score demonstrated a degree of PQD-predicting accuracy that, as evaluated by statistical (discrimination and classification) methods, was higher than those obtained from any of the individual candidate parameters. The 21 PQD participants treated with β-glucan demonstrated good receptibility and a time-dependent improvement in PQD status as evidenced by the decrease of PQD participant to 9.5% at the end of study. CONCLUSIONS This study demonstrated the effect of proof-of-concept of β-glucan on improving PQD and the proof-of-concept of a multivariate-model-derived diagnostic PQD risk score. It also indicated feasibility for future definitive studies. Studies like this embody an innovative approach that uses therapies derived from the mainstream biomedicine to enrich therapeutics guided by CM principle. (Trial registration No. NCT03829228).