Casp8p41 is a protein fragment generated by cleavage of procaspase 8 by human immunodeficiency virus (HIV) protease. We measured Casp8p41 content in memory CD4 T cells and analyzed the association of Casp8p41 content with CD4 T cell count, cross-sectionally and longitudinally. Casp8p41 content was inversely correlated with CD4 T cell count, and change in Casp8p41 content was associated with absolute CD4 T cell count with change over time. Casp8p41 change was a better predictor of CD4 T cell count change than activated CD8 T cell percentage or viral load and was comparable to bacterial 16s DNA levels. This suggests that Casp8p41 is a relevant mediator of CD4 T cell death during HIV infection.