Clinical trials and laboratory studies involving the administration of oral health treatments and foods have benefited from the observance of the so-called crossover study design. Field experience and a growing number of laboratory experiments have shown, however, that ‘blind’ reliance on crossover designs may in some instances lead to unexpected results and erroneous conclusions. Some dietary substances, antibiotic agents, and even fluoride applications may have long-term effects that call into question the appropriateness of the washout periods between treatments. Studies have also been conducted on compounds that have turned out to display synergistic effects. When long-term and synergistic effects are simultaneously present in trials involving a crossover design, difficulties may arise in the interpretation of results. This communication uses as an example the long-term clinical and microbiological effects of xylitol and suggests that inclusion of the crossover practice in clinical trials should be separately and carefully contemplated in each instance.