Little is known about the associations of inflammation and depression with telomere length. Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, the current study assessed the effects of inflammation and depression on telomere length in 1141 young adults in the USA. Depression status was assessed from the World Health Organization Composite International Diagnostic Interview and inflammation status was measured based on C-reactive protein (CRP) concentrations. Information on telomere length was obtained using the quantitative polymerase chain reaction method to measure telomere length relative to standard reference DNA (T/S ratio). Unadjusted and adjusted linear and logistic regression models were used to assess the relationship between the tertiles of CRP concentration and the telomere length stratified by the status of depression such as major depression or depressed affect vs. no depression. The adjusted models were controlled for age, family poverty income ratio, race/ethnicity, marital status, physical activity, body mass index, and alcohol drinking status. A significant and decreasing linear trend in telomere length was found as CRP levels increased in men, regardless of the depression status, and women with major depression or depressed affect ( values < 0.05). Among men without depression, those with an elevated CRP level had increased odds of having a shortened telomere length compared to men with low CRP levels after controlling for covariates (adjusted odds ratio 1.77, 95% confidence interval (CI) 1.09-2.90). In women, there was no association between CRP and telomere length, regardless of the depression status. In conclusion, there was a significant and inverse association between inflammation and telomere length according to the depression status in men but not in women. The present findings may be of clinical significance for the monitoring of inflammation levels and depression status as determinants of telomere length.