Background -The combination of statin therapy and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibition markedly lowers low-density lipoprotein cholesterol (LDL-C) and reduces cardiovascular event rates. Whether residual inflammatory risk as measured by on-treatment high sensitivity C-reactive protein (hsCRP) remains an important clinical issue in such patients is uncertain. Methods -We evaluated residual inflammatory risk among 9,738 patients participating in the Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE)-1 and -2 cardiovascular outcomes trials who were receiving both statin therapy and bococizumab, according to on-treatment levels of hsCRP (hsCRPOT) and LDL-COT measured 14 weeks after drug initiation. The primary endpoint was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death. Results -At 14 weeks, the mean percent change in LDL-C among statin treated patients who additionally received bococizumab was -60.5% (95% CI -61.2 to -59.8; p<0.001; median change -65.4%) as compared to 6.6% (95% CI -1.0 to 14.1; p=0.09; median change 0.0%) for hsCRP. Incidence rates for future cardiovascular events for patients treated with both statin therapy and bococizumab according to on treatment levels of hsCRP <1, 1-3, and >3 mg/L were 1.96, 2.50, and 3.59 events per 100 person-years, respectively, corresponding to multivariable adjusted hazard ratios of 1.0, 1.16 (95% CI 0.81 to 1.66), 1.62 (95% CI 1.14 to 2.30) (p-trend=0.001) after adjustment for traditional cardiovascular risk factors and LDL-COT Comparable adjusted hazard ratios for LDL-COT (<30, 30-50, >50 mg/dL) were 1.0, 0.87, and 1.21, respectively (p-trend=0.16). Relative risk reductions with bococizumab were similar across hsCRPOT groups (p-interaction=0.87). Conclusions -In this post-hoc analysis of the SPIRE trials of bococizumab in a stable outpatient population, evidence of residual inflammatory risk persisted among patients treated with both statin therapy and PCSK9 inhibition. Clinical Trial Registration -URL: https://clinicaltrials.gov Unique Identifiers: NCT01975376, NCT01975389.