Soft tissue signs are inadequate to assess pulpal anesthesia during root canal therapy (RCT). The intention of this study was to determine if a negative response to cold testing is a more effective measure to assess pulpal anesthesia compared to soft tissues signs. Using a randomized, blinded, placebo-controlled design, subjects with baseline responsiveness to cold testing were enrolled. Test subjects achieved a negative response to cold testing prior to RCT. Control subjects were given a sham cold test after demonstrating soft tissue signs. Visual analog scale determined pain level. Unadjusted results showed 12% of test subjects experienced pain during RCT compared with 38% of control subjects (N = 83, p = .004, power = 84%). Multiple logistic regression controlled for confounders and effect modifiers, OR = .20 (p = .01). Subjects who achieved a negative response to the cold test were approximately 80% less likely to experience pain during RCT compared to subjects with soft tissue signs of anesthesia alone.