Temporomandibular disorders (TMD) present a public health issue and are one of the most common musculoskeletal conditions causing chronic pain. This study compares the outcomes of occlusal splint therapy in patients with TMD following two different maxillomandibular relationship (MMR) registration techniques. 40 TMD patients were randomly allocated to MMR registration with the Aqualizer system (AQU) or with chin point guidance (CPG) prior to fabricating occlusal splints. TMD symptoms, subjective pain intensity, and quality of life (QoL) were recorded at baseline and after 3 and 6 months. The treatment led to an overall reduction of TMD symptoms in both groups (Conover test, p < 0.00001). TMJ sounds, TMJ pain with palpation and muscle pain with palpation subsided regardless of the type of MMR registration method used (Cohen's d > 0.8). AQU-based occlusal splints led to a better improvement of TMJ pain with maximum opening compared to CPG-based occlusal splints (Cohen's d = 0.9; CPG d = 0.13). In both groups, occlusal splint treatment had little to no effect on correcting lateral mandible deviation or improving restricted jaw opening. After 6 months occlusal splints in both groups had a large effect on improving subjective pain intensity (Cohen's d > 0.8), however, patients reported a higher QoL in the AQU group compared to the CPG group (Mann-Whitney-U-test, p < 0.05). The results of this study support the premise that occlusal splints are effective in relieving pain-related TMD symptoms. The Aqualizer can be considered for determining MMR in cases, where guided registration techniques are not possible.Trial registration: DRKS00031998.