Objective: This study sought to explore the combined impact of depression and inflammation on memory loss among Mexican Americans. Method: Data were analyzed from 381 participants from the Health and Aging Brain study among Latino Elders (HABLE). Fasting serum samples were collected and assayed in duplicate using electrochemiluminesce on the SECTOR Imager 2400A from Meso Scale Discovery. Positive DepE (depression endophenotype) was codified as any score >1 on a five-point scale based on the GDS-30. Inflammation was determined by TNFα levels and categorized by tertiles (1st, 2nd, 3rd). WMS-III LMI and LMII as well as CERAD were utilized as measures of memory. ANOVAs examined group differences between positive DepE and inflammation tertiles with neuropsychological scale scores as outcome variables. Logistic regressions were used to examine level of inflammation and DepE positive status on risk for MCI. Results: Positive DepE as well as higher inflammation were both independently found to be associated with poor memory. Among DepE positive, those who were also high in inflammation (3rd tertile) were found to perform significantly worse on WMS-III LM I (F = 4.75, p = 0.003), WMS-III LM II (F = 8.18, p < 0.001), and CERAD List Learning (F = 17.37, p < 0.001) when compared to those low on inflammation (1st tertile). The combination of DepE positive and placement in the highest inflammation tertile was found to be associated with increased risk for an MCI diagnosis (OR= 6.06; 95% CI = 3.9−11.2, p < 0.001). Conclusion: Higher inflammation along with positive DepE scores showed increased risk for memory loss. Specifically, the highest inflammation group (3rd tertile) exhibited the greatest risk for MCI diagnosis.