The development of a safe, well-tolerated, effective, and reversible male hormonal contraceptive would be a major clinical advance for couples planning their family size and for control of population growth. High-dosage parenteral testosterone (T) esters alone or in combination with a progestogen (eg, depot medroxyprogesterone) have been shown to confer effective and reversible male contraception in clinical trials, but these regimens are associated with weight gain and suppression of serum high-density lipoprotein cholesterol (HDL) levels. We have previously demonstrated that intramuscular T enanthate 100 mg weekly plus oral levonorgestrel (LNG) 125, 250, or 500 microg daily suppresses spermatogenesis to levels associated with effective contraception, but there is a LNG-dosage-dependent effect of weight gain and HDL suppression. We hypothesized that intramuscular T enanthate 100 mg weekly plus a very low dosage of oral LNG would effectively suppress spermatogenesis in normal men without inducing weight gain or HDL suppression. We conducted a randomized trial comparing 6 months of intramuscular T enanthate (100 mg weekly) plus 31.25 microg of oral LNG daily (T+LNG 31; n = 20) or 62.5 microg of oral LNG daily (T+LNG 62; n = 21). The 2 regimens were equally effective in suppressing spermatogenesis to azoospermia, fewer than 1 million sperm/mL and fewer than 3 million sperm/mL (T+LNG 31 [60%, 85%, and 90%] vs T+LNG 62 [62%, 91%, and 95%] for azoospermia, fewer than 1 million and fewer than 3 million, respectively; P = NS). The T+LNG 31 group did not gain weight (0.25 +/- 1.08 kg; P = NS compared with baseline), but the T+LNG 62 group gained 2.5 +/- 0.77 kg (P < .05 compared with baseline). Serum HDL cholesterol levels declined significantly in both groups (percentage decline month 6 of treatment vs baseline: 12.0% +/- 2.6% and 15.1% +/- 3.0%; P < .05 for T+LNG 31 and 62 respectively). Serum low-density lipoprotein cholesterol levels also declined in both groups (percentage decline month 6 of treatment vs baseline: 6.9 +/- 3.9 and 6.0% +/- 4.1%; P < .05 for T+LNG 31 and P = NS for T+LNG 62). There were no clinically significant adverse events or significant changes in hematology or chemistry profiles in either group during the study. We conclude that 1) intramuscular T plus oral LNG has a very potent synergistic effect in suppressing spermatogenesis at LNG dosages equal to or lower than dosages used in common female oral contraceptive regimens and 2) large, long-term contraceptive efficacy trials should be conducted with a variety of androgen-progestogen combinations including long-acting T formulations such as depot T pellets or intramuscular T undecanoate plus depot LNG or very low dosage oral LNG.