There is no universally accepted method to determine effective therapy for central sleep apnea (CSA). Continuous positive airway pressure (CPAP) applied acutely most often does not eliminate apneas and hypopneas. We hypothesized that the application of two or more therapeutic modalities after the diagnostic phase of polysomnography, a multi-modality titration study (MMTS), would identify a successful CSA treatment more often than a standard split-night study (SNS) and obviate the need for additional polysomnograms to determine a successful therapy. We retrospectively analyzed polysomnograms of patients diagnosed with CSA at our Sleep Disorders Center. We defined a therapy trial that resulted in an apnea-hypopnea index < 10 with at least one treatment modality as a therapeutic success. One hundred fifteen patients with CSA were studied. Sixty-six patients (57.4%) underwent a SNS, and 49 patients (42.6%) underwent a MMTS. SNS yielded only 8/66 (12.1%) successes on the first night, whereas a MMTS yielded 19/49 (38.8%) successes (p = 0.001, two-tailed Fishers exact). Patients who underwent a SNS eventually had similar rate of success as patients studied with MMTS (60.6 vs 63.3%, NS), but required more testing. Adaptive servo-ventilation was the most successful modality tested, yielding 36/46 (78.3%) successes. Trials of additional modalities following a failed trial of CPAP often produce a successful option that may guide therapy in patients with CSA. This approach may lead to establishing the diagnosis and treatment plans faster, while reducing unnecessary testing.