Exposure and response prevention therapy in virtual reality (VERP) for patients with obsessive-compulsive disorder (OCD) has been investigated primarily for its effectiveness. This study evaluated an important research gap, the negative and positive side effects of VERP and its safety. Eighty outpatients with contamination- or checking-related OCD were randomized to two conditions: VERP (six weekly sessions) or care as usual (CAU). Assessments were conducted at baseline (t0), 6 weeks after t0 (t1), and 3 months after t1 (t2). General side effects (Negative and Positive Side Effects Questionnaire; NPSE) and those specific to virtual reality (VERP-Specific Side Effects Questionnaire; VEQ) were assessed at t1. Cybersickness (Simulator Sickness Questionnaire; SSQ) was assessed before and after each session. The safety evaluation involved assessing the worsening of OC-symptoms (Reliable Change Index of the Yale-Brown Obsessive–Compulsive Scale; Y‑BOCS) from t0 to t1 and serious adverse events during the intervention. Results indicated no significant clinical symptom deterioration in the VERP group and no adverse events. In total, 47% of participants in both groups experienced at least one side effect, with significantly fewer reported in the VERP than in the CAU group (p < 0.001). Concerning VERP-specific side effects, at least one side effect was found in 55% of the patients. The SSQ total score did not significantly change from before to after the VERP sessions (p = 0.098, Cohen’s d = 0.297). In conclusion, VERP was safe and demonstrated few side effects, highlighting its potential as a well-tolerated and safe intervention for patients with OCD.