Aprotinin is a collagenase inhibitor previously shown to be effective for treating tendinopathies but associated with systemic allergic reactions. This historical cohort study aimed to determine whether or not the injection regime used affected the risk of allergic reaction and outcome. It compared 223 tendinopathy cases (group R) generally treated with a rapid series of aprotinin injections spaced one to two weekly and 158 cases (group D) generally given a single injection or a delay in their repeat injection(s) of over 6 weeks. Side effects and outcome measures were documented by questionnaire with a response rate of 75%. Systemic allergic reactions occurred in 7% of group R cases compared with 2% in group D (NS). Injections given 2-4 weeks after a previous injection were significantly more likely to lead to allergic reactions (6%) than initial injections (0.3%) and injections given >6 weeks after a previous injection (0.9%) (P<0.05). Overall patient rated satisfaction and outcome measures were similar between groups. In summary the current published regime of multiple aprotinin injections over a period of a few weeks has a fairly high rate of systemic allergic reactions. This can be reduced by minimising repeat injections and recommending a delay of at least 6 weeks between injections. Practitioners using aprotinin must have available facilities to treat anaphylaxis.