Abstract Background and aims High-sensitivity C-reactive protein (hs-CRP) levels and metabolic syndrome (MetS) are known to be associated with an increased incidence of different cancers. We aimed to evaluate the effect of MetS combined with high hs-CRP levels on the risk of primary liver cancer (PLC). Methods Participants were recruited from the Kailuan cohort study and were classified into four groups according to the presence or absence of MetS and inflammation (hs-CRP ≥ 3 or < 3 mg/L). The associations of MetS and inflammation with the risk of PLC were assessed using Cox proportional hazards models. Results This study included 92,770 participants. The mean age was 51.4 years old. Over a median follow-up of 13.02 years, 395 participants were diagnosed as PLC. Compared to the control participants without inflammation (hs-CRP < 3 mg/L) and MetS ( n  = 69,413), participants with high hs-CRP levels combined with MetS ( n  = 2,269) had a higher risk of PLC hazard ratios (HR) 2.91; 95% confidence interval (CI), 1.77–4.81, and participants with high hs-CRP levels and without MetS ( n  = 14,576) had the same trend (HR, 1.36; 95%CI, 1.05–1.75). However, participants with low hs-CRP levels and MetS ( n  = 6,512) had no significant association with an elevated risk of PLC (HR, 1.18; 95%CI, 0.76–1.82). After excluding participants who had cancer during the first year of follow-up, sensitivity analysis showed the same trend. In addition, co-occurrence of MetS and high hs-CRP levels had significant interactive effects on the risk of PLC between the sexes ( P  < 0.001) and the patients with HBV infection ( P  = 0.012). Conclusions Participants with co-occurrence of MetS and high hs-CRP levels have an elevated risk of PLC. Trial registration Kailuan study, ChiCTR–TNRC–11001489. Registered 24 August, 2011-Retrospectively registered, http://www.chictr.org.cn/showprojen.aspx?proj=8050