Background: Polysubstance use (PSU) is common among patients with cannabis use (CU) and is related to more severe CU problems. However, it is unclear how PSU predicts CU treatment outcomes beyond CU patterns. We examined the frequency, amount, and class of additionally used substances as predictors for primary and secondary outcomes. Methods: We conducted crude and adjusted regression analyses for PSU variables as predictors of remission, abstinence, reduction, and secondary outcomes in 166 help-seeking patients from a randomized clinical trial of CANDIS, a cognitive behavioral treatment program. Results: Patients with recent illegal PSU experienced more difficulties in reducing their CU (B = –1.22, p < 0.001). In contrast, remission rates were slightly higher in patients with a wide variety of last-year-PSU (RD = 0.04, p < 0.001). Amphetamine use predicted poorer outcomes regarding CU-related problems (B = –4.22, p = 0.019), and the use of opiates, inhalants, and dissociative substances predicted poorer physical health outcomes (B = –0.62, p = 0.009; B = –0.96, p = 0.039; B = –1.18, p = 0.007). Conclusions: CU treatment is also effective for patients with moderate PSU. However, treatment effects may be enhanced by addressing specific PSU characteristics as part of a modularized program.