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The prognostic value of alkaline phosphatase (AP) measured before and after chemotherapy, but before surgery was established in a retrospective survey of patients. The patients were 18 years or older, with non-metastatic high-grade osteosarcoma. Pre-chemotherapy AP was available in 89 cases, post-chemotherapy AP in 86 patients, and both in 71 cases. AP was classified as Normal (< 100% upper limit), High (100% < or = AP < 200%) or Very High (AP > or = 200%). Osteosarcoma subtype was predominantly conventional. No correlation was found between subtype and chemotherapy response, local recurrence or survival. Pre-chemotherapy AP was raised more in the osteoblastic subtype. Post-chemotherapy AP and normalisation were the same among different subtypes. AP was not correlated with local recurrence. Normal or High pre-chemotherapy AP correlated with better survival at 10 years (64% and 70%) than Very High pre-chemotherapy AP (37%, P = 0.005). Post-chemotherapy AP correlated with survival (68%, 39% and 25% in the Normal, High and Very High group, P = 0.0007) and response to chemotherapy (P = 0.049). A pre-chemotherapy AP above twice Normal correlated with worse survival. If AP decreased after chemotherapy, but was still raised, survival was better, but still worse than if AP normalised. A raised post-chemotherapy AP predicts poor chemotherapy response.