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Objective: To compare the effectiveness of "semiocclusive dressing (SOD)" treatment using plastic wrap or low-adherent absorbent wound dressings with that of occlusive dressing (OD) treatment for National Pressure Injury Advisory Panel stage III/IV pressure injuries in the inflammatory phase. Approach: This 12-week, open-label, randomized controlled trial was conducted at one hospital and three care facilities. Seventy-seven participants were enrolled; 40 comprised the SOD group and 37 comprised the OD group. The primary outcome was the surface area reduction. Secondary outcomes included the Bates-Jensen Wound Assessment Tool (BWAT) score reductions, incidence of adverse events, and material cost. This trial met the recommendations of the CONSORT 2010 statement. Results: The surface area reduction of the SOD group was greater than that of the OD group throughout the study period. The significant interaction was revealed between treatment and time course ( p < 0.0001). The 95% confidence interval of the difference at 12 weeks was 3.4 to 21.9. The median BWAT score reduction of the SOD group at 12 weeks was 23, and that of the OD group was 18.5 ( p = 0.0077). The incidence of adverse events was comparable between groups. The OD treatment cost was 3.0 times higher than the SOD treatment cost ( p = 0.0012). Innovation: Because the SOD does not completely occlude the wound, excess exudate drains from the wound. Therefore, SOD can treat the wound with abundant exudate effectively and safely. Conclusion: SOD treatment is more effective and less expensive than OD treatment for stage III/IV pressure injuries. Clinical Trial Registration: UMIN Clinical Trials Registry [UMIN000023412]. Registered on July 31, 2016.