Concerns about dependence on prescribed analgesia may compromise pain management, but there was previously little reliable evidence about substance dependence among patients with sickle cell disease (SCD). We conducted in-depth, semi-structured interviews with SCD patients in London, UK, to assess DSM-IV symptoms of substance dependence and abuse. Criteria were applied to differentiate between pain-related symptoms, which corresponded to the DSM-IV symptoms but involved analgesics used to control pain, and non-pain-related symptoms, which involved analgesic use beyond pain management. Pain-related symptoms are informative about how the pattern of recurrent acute pain in SCD may make patients vulnerable to perceptions of drug dependence. Non-pain-related symptoms are informative about more stringently defined dependence on analgesia in SCD. Inter-rater reliability was high, with mean Kappa coefficients of 0.67-0.88. The criteria could be used to assess analgesic dependence in other painful conditions. Pain-related symptoms were more frequent, accounting for 88% of all symptoms reported. When pain-related symptoms were included in the assessment, 31% of the sample met the DSM-IV criteria for substance dependence, compared with only 2% when the assessment was restricted to non-pain-related symptoms. Qualitative analysis of participants' descriptions of analgesic use showed that active coping attempts (attempts to anticipate pain and avoid hospital admissions) and awareness of dependence were themes in descriptions of both pain-related and non-pain-related symptoms. Seeking a more normal lifestyle and impaired activities were themes associated with pain-related symptoms. Psychological disturbance was a theme associated with non-pain-related symptoms. The implications are for more responsive treatment of pain in SCD and greater awareness of how patients' pain coping may be perceived as analgesic dependence. Further research could examine ways that pain-related and non-pain-related symptoms of dependence may be associated with other pain coping strategies and with the outcomes of treatment for painful episodes in hospital.