Background Chronic prurigo (CPG) presents with pruriginous lesions and reduced quality of life (QoL). Established treatment options are often unsatisfying. Little is known about efficacy of topical occlusive treatments. Patients often report rapid relief of symptoms when using topical occlusive zinc oxide patches (ZOP). We therefore aimed to assess efficacy of ZOP. Methods In this randomized controlled split-body crossover study, 22 participants were analyzed receiving three treatments sequentially: ZOP, topical betamethasone 17-valerate (TGC), and both ZOP and TGC combined (ZOP+TGC). Each intervention was applied to either right or left side of the body for seven consecutive days. Outcomes were count of active excoriated pruriginous lesions (APL), itch, recurrence of APL, QoL, and treatment comfort. They were assessed through photographs and questionnaires: modified Prurigo Activity and Severity Score (mPAS), modified Itchy Quality of Life Questionnaire (mItchyQoL) and Therapy Comfort Score (TCS). Results We observed significant reduction of 46% in APL count for ZOP (95% CI from 30% to 58%, p-value: < 0.0001). Similar reduction was seen for ZOP+TGC, lower reduction for TGC alone (48% [95% CI from 33% to 60%, p-value: < 0.0001] vs 26% [95% CI from 4% to 43%, p-value: 0.02]). APL counts on the non-treated side remained stable. Significant reduction in itch was observed after all treatments with largest improvement for ZOP+TGC, followed by TGC and lastly ZOP alone (-2.3 units [95% CI from -3.5 to -1.1, p-value: 0.00015] vs -1.5 units [95% CI from -2.8 to -0.3, p-value: 0.01 vs -1.4 units [95% CI from -2.6 to -0.2, p-value: 0.02]). QoL increased significantly after ZOP+TGC as well as after TGC (-8.3 units [95% CI from -13.6 to -3.1, p-value: 0.0018] vs -5.7 units [95% CI from -10.9 to -0.5, p-value: 0.03]). Good subjective response concerning treatment comfort was observed. Conclusion ZOP are effective in reducing APL after one week of treatment. Adding TGC to ZOP did not add considerable benefit in reducing APL. All three treatments reduced itch and improved QoL with largest improvement shown by ZOP combined with TGC. Patients tolerated ZOP well and reported no adverse events. We therefore suggest ZOP combined with TGC as an effective, fast-acting, low-cost treatment for reducing APL and itch in patients with CPG.