Definitive risk factors for the development of adult T-cell leukemia (ATL) among asymptomatic human T-cell leukemia virus type I (HTLV-1) carriers remain unclear. Recently, HTLV-1 proviral loads have been evaluated as important predictors of ATL, but a few small prospective studies have conducted. We prospectively evaluated 1218 asymptomatic HTLV-1 carriers (426 males and 792 females) who were enrolled during 2002–2008. The proviral load at enrollment was significantly higher in males than females (median, 2.10 vs 1.39 copies/100 PBMC) (P < .0001), in those aged 40–49 and 50–59 years than that of those aged <40 years (P = .02 and .007, respectively), and in those with a family history of ATL than those without the history (median, 2.32 vs 1.33 copies/100 PBMC) (P= .005). During follow-up, 14 participants progressed to overt ATL. Their baseline proviral load was high (range, 4.17–28.58 copies/100 PBMC). None developed ATL among those with a baseline proviral load lower than approximately 4 copies. Multivariate Cox analyses indicated that a higher proviral load was an independent risk factor for progression of ATL from carrier status. Next we tried to determine risk-indicator genes. In this study, whole genome gene expression profiling was conducted in ATL patients (n=52), HTLV-1 carriers (n=40), and in healthy volunteers (n=21). Five carriers, who later developed ATL were included as “high-risk carriers”. Comparative analyses in terms of diagnosis, proviral load, ATL types, and risk among carriers allowed us to determine potential risk-indicator genes of ATL, including CCR4, CTLA4, MALT1, cMyb, and IL21R, all of which play central roles in regulation of T-cell functions and cell proliferation. Studies are in progress to test if they indeed reflect the transition of cellular phenotypes toward ATL.