Objectives: To identify managerial and organizational characteristics of multi-specialty medicine wards and individual characteristics of health professionals that are most strongly associated with clinical practice guidelines (CPG) adherence. Design: Cross-sectional stratified cluster sample design. Setting: Data were gathered from 36 randomly selected multi-specialty medicine wards. Participants: The study population included all health professionals involved in patient care working in the participating wards. Main outcome measures: The degree of CPG adherence was measured using clinical vignettes on three topics: pain management, managing heart failure and managing diabetes. Responses from each professional to each clinical case were quantified using a 10-point scale. Managerial and organizational characteristics of medical department and individual characteristics of health professionals were obtained using three questionnaires. Results: The study sample consisted of 859 professionals (362 orderlies, 361 nurses and 136 physicians). Factors independently and positively associated with CPG adherence were (i) individual factors: low age of professionals, expertise in diabetology and activity in cardiology; (ii) organizational and managerial factors: good understanding between physicians and other personnel; and (iii) structural factors: computer-based test results and prescriptions, presence of medical specialists, inter-department mobility of orderlies, medium-length stay (between 7 and 10 days) and large bed capacity. Conclusions: Good CPG adherence in general medicine needs institutional dynamism, availability of clinical competence and team culture based on cooperation.