An enzyme‐linked immunosorbent assay for measuring type I collagen degradation products in serum (S‐ELISA) was developed. The assay uses a high affinity polyclonal antibody which reacts with an isomerized form of an 8 amino acid sequence of the C‐telopeptides of type I collagen (EKAHD‐β‐GGR). Cross‐reactivity to a nonisomerized synthetic peptide form of the 8 amino acid sequence is less than 0.2%. Values obtained in a group of premenopausal women (age, 33.3 ± 3.11 years) were 69 ± 24 ng/ml (n = 22). In a group of early postmenopausal women (age, 51.8 ± 1.88 years) values obtained were 125 ± 43 ng/ml (n = 46), which represents an increase of 81% (p < 0.001). Values found in untreated patients with Paget's disease were 234 ± 95 ng/ml (n = 15), and for primary hyperparathyroidism we found 335 ± 82 ng/ml (n = 10). Interveneous administration of a bisphosphonate (Pamidronate) to Paget's disease patients for 3 days was reflected in the S‐ELISA by a decrease in the values of 55% when compared with values before treatment (n = 15). Following treatment with another bisphosphonate (Alendronate) for 6 months, values were decreased to 48 ± 19 ng/ml (n = 12), which corresponds to a 62% decrease. Clinical results presented in this context support that the assay is a sensitive and specific index of bone resorption. It may, therefore, prove useful in the follow up of treatment of patients with metabolic bone diseases and in the clinical investigation of osteoporosis.