Background: In the United States, the prevalence among adults of palpable thyroid nodules is 4%-7%, of which 5%-10% may represent thyroid carcinoma. Despite the success of fine-needle aspiration in reducing the need for thyroidectomy, aspirates are inadequate to render a diagnosis in 20% of cases. Minimizing nondiagnostic samples is an important goal in improving this technique. Our objective was to determine whether bedside-prepared slides improve diagnostic adequacy over standard solution-based samples. We further sought to determine the role of needle size. Methods: One hundred sixty-two patients were prospectively enrolled. For each, both bedside slides and standard cytology solutions were prepared; the order of preparation alternated from subject to subject. Needle size (21- or 25-gauge) also alternated from subject to subject. Slides were evaluated by pathologists blinded to needle size. The study took place in the endocrinology clinic at Boston Medical Center, the tertiary referral hospital of the Boston University School of Medicine. Key outcomes were diagnostic adequacy and specimen cellularity. Results: Compared to standard solution-based samples, bedside slides provided more cellular specimens (p < 0.01) and fewer nondiagnostic samples (p = 0.016). When standard solution-based samples were used as the sole method of preparation, 21-gauge needles provided improved diagnostic adequacy. Conclusions: Bedside-prepared slides offer improved diagnostic adequacy and specimen cellularity over solution-based samples. The difference may be especially important when using smaller (25-gauge) needles to perform fine-needle aspiration. When solution-based samples are used, larger (21-gauge) needles provide more diagnostic specimens.