PURPOSE: Conducting studies in national practice-based research networks presents logistic and methodologic challenges. Pediatric Research in Office Settings (PROS) has learned valuable lessons in implementing new strategies and adapting to challenges. We describe practical challenges and results of novel applied strategies in implementing and testing the Clinical Effort Against Secondhand Smoke Exposure (CEASE) intervention as part of a national-level cluster-randomized controlled trial. METHODS: In the trial, 20 PROS practices were randomized to either a CEASE intervention arm or a control arm. Parents of children seen in the office who indicated smoking in the past 7 days were asked to complete a postvisit enrollment interview and telephone interviews 3 and 12 months later. Identified challenges included (1) recruiting 20 practices serving a high percentage of parent smokers; (2) screening all parents bringing children for visits and enrolling eligible parents who smoked; and (3) achieving an acceptable 12-month telephone response rate. RESULTS: A total of 47 interested practices completed the Practice Population Survey, of which 20 practices in 16 states completed parent enrollment. Thirty-two research assistants screened 18,607 parents and enrolled 1,980 of them. The initial telephone interview response rate was 56% at 12 months, with incorrect and disconnected numbers accounting for nearly 60% of nonresponses. The response rate rose to 67% after practices supplied 532 new contact numbers and 754 text messages were sent, with 389 parents completing interviews. CONCLUSION: The strategies we used to overcome methodologic barriers in conducting a national intervention trial allowed data collection to be completed in the office setting and increased the telephone interview response rate.