Summary Background Hepatitis B surface antigen (HBsAg) seroclearance is the most important milestone indicating favourable clinical outcomes in patients with chronic hepatitis B (CHB). However, it is difficult to achieve due to the impaired HBV‐specific immunity, such as programmed cell death 1 (PD‐1)‐associated T cell exhaustion. We assessed soluble PD‐1 (sPD‐1) as a novel seromarker for predicting spontaneous HBsAg loss. Methods Serial serum levels of sPD‐1 were evaluated in 1046 untreated hepatitis B e antigen (HBeAg)‐seronegative individuals who had achieved undetectable serum HBV DNA. Multiple regression analyses were applied to assess associations among baseline and subsequent sPD‐1 levels, HBsAg decline during follow‐up, and spontaneous HBsAg seroclearance. Results A total of 390 individuals achieved spontaneous HBsAg seroclearance during 6464.4 person‐years of follow‐up. Baseline sPD‐1 levels were inversely associated with baseline HBsAg levels (qHBsAg) as well as a greater decline in qHBsAg during follow‐up. Incidence rates of HBsAg seroclearance were 11.5, 61.7, 96.7 and 151.0 per 1000 person‐years for sPD‐1 levels of ≥4000, 536‐3999, 125‐535 and <125 pg/mL, respectively (Ptrend < 0.0001). Compared with baseline sPD‐1 levels ≥4000 pg/mL, the rate ratio (95% CI) of HBsAg seroclearance was 2.1 (1.1‐3.9), 3.0 (1.6‐5.5) and 5.1 (2.8‐9.5), for baseline sPD‐1 levels of 536‐3999, 125‐535 and <125 pg/mL, respectively, after adjustment for sex, age and serum alanine aminotransferase and HBsAg levels. Conclusion sPD‐1 level is a novel marker which independently predicts spontaneous HBsAg seroclearance of HBeAg‐negative inactive CHB patients with undetectable HBV DNA. (word count: 234, <250). Serum soluble programmed cell death 1 levels inversely predict spontaneous functional cure in inactive carriers with chronic hepatitis B.