Abstract: Phase I of the Zurich Prometheus Study is a cross-sectional study focusing on an up-to-date serology for HIV and hepatitis B/C and associated risk factors for all clients in four participating clinics offering opiate substitution in Zurich, Switzerland. The mean age of the 603 respondents is 30.7 years (SD=6.2), and 38% of them are women. Seventy-five percent of the respondents have a history of injecting drug use (IDU), and over half have injected within the past six months. Lab-confirmed seroprevalence for HBV (50%) and HCV (57%) is twice that of HIV (24%). There is an 80% risk reduction for all three viral infections among those starting IDU after 1991—when harm reduction efforts were in full swing—compared to those who began before 1988—before clean needles were widely available. These findings suggest a strongly protective effective of harm reduction measures. But while a stabilization in HIV prevalence at 15% can be seen among drug users who started injecting after 1991, prevalence rates for HBV and HCV still remain several times higher. The prevalence data in this study support data showing continued high incidence rates for HBV and HCV, even among new injectors in the harm reduction era.