Purpose: Appalachian counties have historically had elevated infant mortality rates. Changes in infant mortality disparities over time in Appalachia are not well-understood. This study explores spatial inequalities in white infant mortality rates over time in the 13 Appalachian states, comparing counties in Appalachia with non-Appalachian counties. Methods: Data are analyzed for 1,100 counties in 13 Appalachian states that include 420 counties designated as Appalachian by the Appalachian Regional Commission. Area Resource File data for 1976-1980 and 1996-2000 provide county- and city-level infant mortality rates, poverty rates, rural-urban continuum codes, and numbers of physicians per 1,000 residents. Multiple regression analyses evaluate whether Appalachian counties are significantly associated with elevated white infant mortality in each time period, accounting for covariates. Findings: White infant mortality rates decreased substantially in all sub-regions over the last 2 decades; however, disparities in infant mortality did not diminish in Appalachian counties compared to non-Appalachian counties. After accounting for poverty, rural/urban status, and health care resources, Appalachian counties were significantly associated with comparatively higher infant mortality during the late 1970s but not in the late 1990s. At the more recent time point, higher poverty rates, residence in more rural areas, and lower physician density were associated with greater infant mortality risk. Conclusion: Appalachian counties continue to experience relatively elevated infant mortality rates. Poverty and rurality remain important dimensions of health service need in Appalachia.