Background: Despite the recognition of problem drug use as a significant public health issue, little is known about the pattern of comorbidity in people with substance use disorders (SUD) in Nigeria. Aim: This study evaluated comorbidity and associated clinico-demographic factors of problem drug use at a tertiary hospital in Lagos, Nigeria. Materials and Methods: The study participants consisted of 83 inpatients admitted over a period of one year into the drug rehabilitation ward of Lagos University Teaching Hospital (LUTH), Lagos, Nigeria. A retrospective review of their case notes was done to extract relevant data in line with the study objectives. The participants included in the study had diagnoses of harmful use or dependence syndrome. Data analyses were done using Statistical Package for Social Sciences (SPSS-17). Results: Problem drug users (PDU) were mostly males 77/83 (92.8%), single 77/83 (92.8%) and unemployed 46/83(55.4%). Majority 59/83(71.1%) abused multiple substances, with cannabis use disorder diagnosed in sixty-one participants. Close to half of PDU 39/83(47.0%) commenced drug use in late adolescence. Mental comorbidity occurred in (46/83)55.4% of PDU, majorly (42/46) among those with cannabis use disorder. Of those with mental comorbidity, schizophrenia was associated with cannabis use disorder (p=0.02), and not with opioid or other stimulants use disorders (p<0.01, p=0.03 respectively). Somatic comorbidity occurred in 19.2% (16/83) of participants, and sickle cell disease accounted for one-quarter (4/16) of them. Of those with somatic comorbidity, (6/16) was diagnosed with opioid use disorder, while all participants with comorbid sickle cell disease (4/4) abused opioids. Conclusions: Findings in this study suggest the need to be cognizant of potential mental and somatic comorbidity among those with SUD, and provide guidance for future hypothesis-driven research.