Men and women differ in thyroidal C-cell mass and calcitonin secretion. This difference may have implications for the definition of calcitonin thresholds to distinguish sporadic C-cell hyperplasia from occult medullary thyroid cancer. This retrospective study examined the hypothesis that gender-specific calcitonin thresholds predict occult medullary thyroid cancer more accurately among patients with increased basal calcitonin levels than unisex thresholds. A total of 100 consecutive patients were evaluated with occult sporadic C-cell disease no larger than 10 mm who were referred for increased basal calcitonin levels and underwent pentagastrin stimulation preoperatively at this institution. Altogether, gender-specific calcitonin thresholds predicted medullary thyroid cancer better than unisex thresholds. At lower (≤50 pg/ml basally; ≤500 pg/ml after stimulation), but not higher, calcitonin serum levels, women revealed medullary thyroid cancer four to eight times more often than men. Most discriminatory between C-cell hyperplasia and medullary thyroid cancer was a basal calcitonin threshold of 15 pg/ml (corrected 20 pg/ml) for women and 80 pg/ml (corrected 100 pg/ml) for men, based on the greatest accuracy at the lowest possible calcitonin level. The respective gender-specific stimulated peak calcitonin thresholds were 80 pg/ml (corrected 100 pg/ml) and 500 pg/ml. Corresponding positive predictive values for medullary thyroid cancer at these calcitonin thresholds were 89 and 90% for women, as opposed to 100% for men. To increase the positive predictive value for women to 100%, the respective calcitonin thresholds would have to be raised to 40 pg/ml (corrected 50 pg/ml) and 250 pg/ml. These findings indicate that gender-specific calcitonin thresholds predict sporadic occult medullary thyroid cancer better than unisex thresholds.