Objectives: To determine the impact of animated spokes-characters on the effectiveness of direct-toconsumer (DTC) advertising (attitude towards ad, brand, company, spokes-characters, attention paid to the ad, drug inquiry intention, and perceived product risk) and consumers’ involvement in moderating the effects of spokes-characters on advertising effectiveness. Methods: In a randomized post-test only study, using the Elaboration Likelihood Model, consumers’ responses to animated vs. non-animated (human) spokes-characters in a fictitious DTC ad were recorded using online surveys (n = 490). Data was analyzed using a 2 (spokes-characters type: animated/human) x 2 (involvement: high/low) factorial MANCOVA. Results: After controlling for the effects of the covariates, results of the MANCOVA indicated significant main effects of spokes-characters type and involvement on the dependent variables. There was no significant interaction effect between spokescharacters type and involvement. Consumers only differed on their attitude towards the spokes-characters between the two spokes-character types. Except for perceived product risk, consumer’s involvement had a significant influence on the remaining ad effectiveness variables. Conclusion: Consumers demonstrated more favorable attitudes towards the human spokes-character compared to the animated spokes-character. Apart from perceived product risk, high involvement consumers demonstrated more favorably to the remaining ad effectiveness variables compared to low involvement consumers, and exhibited significantly strong drug inquiry intentions during their next doctor visit. Further, consumers’ involvement did not act as a moderator variable.