Maintenance monotherapy with lopinavir/ritonavir (LPV/r) is a safe and effective strategy in the short and medium term. To evaluate its effectiveness in the long term, the question of whether a theoretical decrease in the potency of treatment could reduce suppression of viral replication in reservoirs or in biological compartments where LPV/r penetration is lower must be answered. LPV/r penetrates fairly well in the most impenetrable reservoir, the central nervous system. However, the ability to penetrate reservoirs is not essential to achieve efficacy, since the main battlefield in the fight against HIV is the plasma compartment. What can be achieved in this compartment with antiretroviral therapy can be faithfully extrapolated to cerebrospinal fluid and almost always to seminal fluid. What occurs in lymphoid tissue and in intestinal mucosa, whose physiopathology is intensely initiated at the beginning of the disease, is more obscure and difficult to interpret. The marginal problems that might be generated by some reservoirs that harbor HIV and are relatively impermeable to LPV/r would be of little importance in simplification therapy, which is only offered as maintenance monotherapy with LPV/r to clinically stable patients with good immunological and virological control.