In order to determine if the expression of the activation marker CD38 can correlate with HIV disease progression independently of cycling, we performed a cluster-based multivariate correlation analysis of total circulating CD4(+) T cell counts and viral loads with frequencies of CD38 and Ki67 expression on CD4(+) lymphocytes from patients with untreated HIV infection, stratified in maturation subpopulations, and subpopulation subsets defined by the expression of CXCR5, CXCR3, and CCR4. The frequencies of the activated phenotypes %CD38(+) Ki67(-) and %CD38(+) Ki67(+) of the CXCR5(-) CXCR3(-) CCR4(+) ("pre-Th2") central memory (T(CM)) cell subset clustered together, comprising a significant negative correlate of total circulating CD4(+) T cell counts and a positive correlate of viral load in multivariate analysis. Frequency of cycling-uncoupled CD38 expression in "pre-Th2" T(CM) cells was a negative correlate of total circulating CD4(+) T cell counts in univariate analysis, which was not the case of their %CD38(+) Ki67(+). CXCR5(+) CXCR3(-) CCR4(-) T(CM) cells were underrepresented in patients, and their absolute counts correlated negatively with their %CD38(+) Ki67(-) but not with their % CD38(+) Ki67(+). Our results may imply that CD38 expression either reflects or participates in pathogenic mechanisms of HIV disease independently of cell cycling.