Pharmacotherapy has been used as an adjunct to CPAP for treatment of residual excessive sleepiness in patients with a diagnosis of obstructive sleep apnea syndrome (OSAS). However, no studies with a high level of evidence have been conducted to support this practice and confirm its effectiveness. We conducted a meta-analysis to summarize and quantify the effects of pharmacological treatment in adults with OSAS who experience residual excessive sleepiness despite adequate CPAP use. We reviewed clinical trials that compared medications to placebo and evaluated the outcomes residual excessive sleepiness, cognition, and quality of life, as well as treatment effectiveness and safety. The MEDLINE, EMBASE, LILACS, Cochrane Central Register of Controlled Trials – CENTRAL, and PsycINFO electronic databases were searched using highly sensitive search strategies. Trials were only included if measures were taken to ensure effective CPAP treatment. Eight randomized clinical trials were included. Pharmacotherapy with modafinil and armodafinil led to improvement of excessive daytime sleepiness, attention/alertness, and clinical condition as measured with the CGI-C. No improvements in quality of life or other cognitive domains (including memory, executive function, and language) could be confirmed. Pharmacotherapy did not cause any severe adverse effects, but was associated with significant dropout rates as compared with placebo. In conclusion, although our results demonstrate the effectiveness of pharmacological treatment as an adjunct to CPAP, further investigation is necessary to improve confidence in its effects. Many findings on the impact of pharmacotherapy on cognition and quality of life were evaluated through analysis of single studies, with heterogeneity in tests and absence of standardization, which reduced certainty as to whether actual improvement occurred in these outcomes.