The objective of this study was to examine the factor structure and longitudinal measurement invariance of the Center for Epidemiological Studies Depression Scale (CES-D). The population-based sample included 347 adult women who had children participating in the Health-related Quality of Life in Children with Epilepsy Study. Longitudinal confirmatory factor analysis was used to confirm the factor structure and test for measurement invariance. The original CES-D four-factor model (depressed affect, positive affect, somatic activity, and interpersonal relations) provided the best fit to the data compared to alternate models: [χ(2) = 362.95 (df = 164); Comparative Fit Index (CFI) = 965; Tucker-Lewis Index (TLI) = 0.960; Weighted Root Mean Square Residual (WRMR) = 0.966; Root Mean Square Error of Approximation (RMSEA) = 0.059, 90% confidence interval (CI), 0.051, 0.068] and was used for invariance testing. Results suggested full measurement invariance over time with the final model demonstrating adequate fit [χ(2) = 2303.92 (df = 1,776); CFI = 0.957; TLI = 0.952; WRMR = 1.149; RMSEA = 0.033, 90% CI, 0.030, 0.038]. We conclude that the four-factor structure of the CES-D is supported for adult women and that the measurement of the scale is longitudinally invariant. Clinicians and researchers can be confident that longitudinal changes in CES-D scores reflect true changes in depressive symptomatology and are not an artifact of changes in the interpretation of items in the scale over time.