People typically attribute more responsibility to those individuals who are infected with sexually transmitted diseases (STD) than other diseases. This study tested how different routes (i.e., sexually transmitted or foodborne) of transmission have an impact on individuals’ general perception on stigma/shame and the attributions of responsibility, when controlling for symptoms/conditions of the hypothetical virus infection. Two hundreds and ninety eight college students were recruited for the study. As predicted, people who were attributed with control over contracting the virus (i.e., sexually transmitted route) were likely to be assigned a greater level of personal responsibility and were more likely to receive blame from others than people who were attributed relatively less control over contracting the virus (i.e., foodborne). The relationship between the attribution of responsibility and communication efficacy was also assessed. The results supported our prediction that there was a significant association between the attribution of responsibility and communication efficacy, in that the perceived controllability of the situation, perceived responsibility for the situation, and blame were all significantly correlated with communication efficacy in a negative direction. Practical applications by evaluating the effectiveness of the actual Merck’s Gardasil advertisement were discussed that the Gardasil advertisement appears to reduce the perceived shame and stigma associated with the sexually transmitted nature of the virus by not revealing the true nature of the virus upfront.