The aim of this study was to examine whether increases in severity of subclinical inflammation, measured by high-sensitivity C-reactive protein (hs-CRP), increased experimental pain sensitivity, measured by cold-pressor tolerance, and to test whether this relationship is independent of chronic pain. A large population-based study from 2007 to 2008, the sixth Tromsø Study, provided data from 12,981 participants. For the present analysis, complete data for 10,274 participants (age: median 58 years) were available. The main outcome measure was cold-pressor tolerance, tested by placing the dominant hand in circulating cold water (3°C) for a maximum of 106 seconds. Cox proportional hazard models, treating hand withdrawal during the cold-pressor test as the event and enduring the full test time as censored data, were used to investigate the relationship between hs-CRP levels (≤3 or >3 mg/L) and cold-pressure tolerance. The fully adjusted model was controlled for age, sex, education, body mass index, smoking status, alcohol consumption, emotional distress, statin usage, and self-reported presence of chronic pain. Additional analysis was performed in participants without chronic pain. Higher levels of hs-CRP were negatively related to cold-pressor tolerance (hazard ratio [HR] = 1.24, 95% confidence interval [CI], 1.12-1.37, P < 0.001), adjusted for age and sex. This relationship remained essentially unaltered after controlling for potential confounders (HR = 1.22, 95% CI, 1.09-1.36, P < 0.001), as well as for the presence of chronic pain (HR = 1.22, 95% CI, 1.09-1.36, P < 0.001). The present data show that subclinical inflammation is related to increased pain sensitivity, suggesting a potential role of inflammation in experimental pain which may be of importance for the development of clinical pain.