This study examined the frequency and extent of detrimental effects of cognitive behavioral therapy (CBT) for psychosis. In a randomized clinical trial, we investigated the efficacy of CBT for the reduction of negative symptoms as compared with cognitive remediation (CR) in schizophrenia patients (n = 198). Safety was addressed through assessment of severe adverse events (SAEs), which were defined as suicides, suicide attempts, suicidal crises, and severe symptom exacerbations over a period of 12 months after inclusion in the study. Monthly assessments with Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms allowed for the analysis of symptom increases during the treatment. There were no suicides in the trial. SAEs were observed in 10 CBT and 5 CR patients. Increases in negative symptoms occurred in 64 CBT and 58 CR patients. These differences were not significant. The maximum increase in negative symptoms under treatment, as compared with the baseline, was equal to an effect size of -0.66 in CBT patients and -0.77 in CR patients. Thus, the SAE rate was comparable between both interventions and was relatively low, given the severity of the psychotic disorder. Therapists should be aware of a subgroup of patients who show symptom increases with large effect sizes and might require more intensive care.