Background: Aspects of the canonical stress response differ in stimulant, opioid, and alcohol users relative to controls, and dysregulated responses to stress may contribute to continued use of these drugs. Little prior research has focused on stress responses in regular cannabis smokers. We assessed responses to a standardized laboratory social stress assay (the Trier Social Stress Task; TSST) in regular cannabis smokers (CANs) compared with controls (CONs). Methods: Healthy, non-treatment-seeking adult CANs (⩾4×/week; smoking cannabis as usual) and demographically matched CONs completed the TSST. Outcome measures were subjective mood, heart rate, and salivary cortisol. Results: Nineteen CANs (1 female) and 20 CONs (2 female) participated; groups were matched on trauma exposure, sex, race, and age. CANs smoked cannabis 6.4 ± 1.1 days/week. Eight CANs and one CON smoked tobacco cigarettes daily. Overall, the TSST produced expected increases in anxiety, negative mood states, cortisol, and heart rate. CANs had blunted subjective response to stress relative to CONs, but they did not differ in physiological (cortisol and cardiovascular) stress responding. Conclusion: These results indicate that CANs have blunted mood responses to social stress, but normative physiological stress responding. Observed differences could be due to residual effects of cannabis, reluctance to endorse negative mood states, or to issues related to identifying (i.e., emotional identification) or feeling (i.e., interoception) stress-related affective states. Further research is warranted to characterize the mechanisms of these differences and assess implications for daily functioning and treatment outcomes.