Introduction: The effect of opioids on driving performance has been much debated. Driving is a complex task requiring integration of psychomotor, cognitive, motor and decision-making skills, visual-spatial abilities, divided attention, and behavioral and emotional control. The objective of this systematic review was to assess the quality of studies and to revisit the concept that patients on stable opioids are safe to drive as it applies to everyday practice. Methods: We searched MEDLINE, EMBASE, PSYCinfo, CENTRAL, TRANSPORT, CINAHL, reference lists of retrieved articles and narrative reviews, for studies on chronic cancer and noncancer pain patients on opioids, tested by driving, driving simulator, or cognitive/psychomotor tests. Methodological quality was assessed with Methodological Index for Nonrandomized Studies, cognitive/psychomotor tests were appraised regarding their sensitivity and validation, and whether confounding variables potentially affecting the study conclusions were recorded. The results were analyzed both quantitatively and qualitatively. Results: We included 35 studies (2044 patients, 1994 controls), 9% of the studies were of poor, 54% of fair, and 37% of high quality; 3 quarters of the studies used high sensitivity cognitive tests. Amount and dose of opioids varied largely in many studies. Mean number of possible but unreported confounders was 2.2 (range, 0 to 4), relating to failure of the studies to mention coprescriptions with psychotropic effects, pain severity, sleep disorder or daytime somnolence, and/or significant depressive or anxiety-related problems. Interpretation: The commonly held concept that "chronic pain patients on stable opioids are safe to drive" cannot be generalized to all such patients in everyday practice, but may be applicable only to a subset who meet certain criteria.