Initial prophylaxis with anticholinergics for neuroleptic-induced extrapyramidal syndromes (EPSs) is controversial. Recommendations, based on conflicting research findings, vary from routine prophylactic use of anticholinergics to withholding these agents until dystonia, akathisia, or parkinsonism develops. To determine whether anticholinergic prophylaxis influenced EPS rates during the first 21 days of neuroleptic treatment, 215 psychotic inpatients were reviewed. Initial prophylaxis with anticholinergic drugs significantly reduced the occurrence of EPSs. This treatment's efficacy depended on a complex interaction of variables, including the patient's sex and age, antipsychotic drug type and dose, and treatment phase.