OBJECTIVES: To compare the analgesic effects of rhomboid intercostal and subserratus plane block (RISS) and rhomboid intercostal block (RIB) on postoperative analgesia in patients undergoing video-assisted thoracoscopic surgery (VATS) for wedge resection. DESIGN: A prospective, randomized study. SETTING: A single-center tertiary surgery center. PARTICIPANTS: Sixty patients with American Society of Anesthesiologists class I-III undergoing VATS wedge resection. INTERVENTIONS: Ultrasound-guided RIB or RISS block implementation. MEASUREMENTS AND MAIN RESULTS: Patients were assigned to the RIB group or the RISS group as part of a multimodal analgesia. In addition to the blocks, multimodal analgesia consisted of paracetamol, tenoxicam, intravenous morphine via patient-controlled analgesia (PCA), and tramadol as a rescue analgesic for both groups, in accordance with the medical literature. Pain scores assessed by the visual analog scale (VAS) at rest and coughing, morphine consumption, rescue analgesic requirements, and side effects were recorded postoperatively for 48 hours. The RISS group had lower VAS scores at rest and with coughing at all time points except 12 hours (for both variables, p < 0.05 at 0 hour and p < 0.01 at 0.5, 1, 2, 4, 8, 24, and 48 hours). The first PCA demand time was significantly longer in the RISS group (p = 0.001). Morphine consumption via PCA was lower in the RISS group at all time points (p < 0.05 at 0 hours and p < 0.01 at 12, 24, and 48 hours). Recovery room stay and mobilization times also were shorter in the RISS group (p < 0.05 for both). Other parameters were similar in the 2 groups. CONCLUSIONS: In this study with a multimodal analgesic approach, RISS provided superior analgesia compared to RIB in patients undergoing VATS for wedge resection.