Objective: To compare self-reported doxycycline compliance in men and women attending an STD clinic with indications for Chlamydia trachomatis treatment to compliance measured using microprocessor-containing medication vials to count each time and date medication vials were opened. A secondary objective was to correlate outcomes of therapy, as measured by symptom resolution and persistence of chlamydial nucleic acids, with measured doxycycline compliance. Methods: Between September 1995 and July 1997, Medication Event Monitoring System (MEMS) caps were used to measure compliance with recommended doxycycline therapy (14 doses over 7 days) in patients treated for presumed C. trachomatis infections. Polymerase chain reaction (PCR) assays for C. trachomatis were performed on urine specimens collected at the time of follow-up evaluation. Results: Of 221 evaluable participants, although 90% reported taking their medication as directed, only 33 (16%) managed this level of compliance according to data obtained from the MEMS cap. Although 144 (65%) patients took more than 11 of 14 doses over 8 days, 147 (67%) participants had at least one interval of 24 hours or longer between doses in an 8-day period. Of 81 participants with positive C. trachomatis cultures at enrollment, follow-up urine PCR for C. trachomatis was positive in 5 (6%). Medication Event Monitoring System data for four of the five patients with positive PCR tests as follow-up showed each had two or more 24-hour intervals when their medication vials were not opened and three of four had opened their vials less than 11 times. Conclusions: This study suggests that few patients take medications as prescribed and that self- report substantially underestimates medication noncompliance. Despite poor compliance, there were few treatment failures.