A cannabis withdrawal syndrome has been characterized, but its clinical significance remains uncertain. One method of assessing the significance of cannabis withdrawal is to compare it directly to an established withdrawal syndrome. The present study was a within-subject comparison of cannabis, tobacco, and combined cannabis and tobacco withdrawal among users of both substances. Participants (N=12) completed three 5-day periods of abstinence in a randomized order, separated by 9-day periods of usual substance use. Overall withdrawal severity associated with cannabis alone and tobacco alone was of a similar magnitude. Withdrawal during simultaneous cessation of both substances was more severe than for each substance alone, but these differences were of short duration and substantial individual differences were noted. These results are consistent with other evidence suggesting cannabis withdrawal is clinically important and warrants detailed description in the DSM-V and ICD-11. Additional research is needed to replicate these findings and to further investigate the effects of abstaining from multiple drugs simultaneously.